Novel amides useful for treating pain

ABSTRACT

The present invention relates to compounds of formula (I-VII) 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, in which A, L, R 6 , R 7  and R 8  are defined herein. The present invention also relates to methods of treating pain using these compounds and pharmaceutical compositions including these compounds.

This is a continuation of U.S. patent application Ser. No. 11/521,807,filed Sep. 15, 2006, which is a divisional of U.S. patent applicationSer. No. 10/887,383, filed Jul. 8, 2004, now U.S. Pat. No. 7,129,235,which claims priority from U.S. Provisional Application Ser. No.60/486,548 filed on Jul. 11, 2003, all of which are incorporated hereinby reference.

TECHNICAL FIELD

The present invention relates to compounds of formula (I-VII) that areuseful for treating pain, pharmaceutical compositions containingcompounds of formula (I-VII) that are useful in treating pain, andmethods of treating pain using compounds of formula (I-VII).

BACKGROUND OF INVENTION

Pain continues to produce severe distress in people's lives, dominatingand disrupting their quality of life. Much of the currently availableclinical treatment is only partially effective and may be accompanied bydistressing side effects or have abuse potential. The unmet clinicalneed, the personal suffering, and societal economic costs of pain aresubstantial. The lack of success in clinical pain therapy exemplifiesthe need for the discovery of new analgesics.

The present invention relates to novel compounds useful as analgesics.

SUMMARY OF THE PRESENT INVENTION

The present invention discloses novel amides, a method for controllingpain in mammals, and pharmaceutical compositions including those amides.More particularly, the present invention is directed to compounds ofgeneral formula (I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

A is

X₁ is N or CR₁;

X₂ is N or CR₂;

X₃ is O or S;

R is absent or O;

R₁ is hydrogen, lower alkoxy, lower alkenyl, lower alkyl, loweralkylthio, lower alkynyl, lower haloalkoxy, lower haloalkyl, lowerhaloalkylthio, halogen, hydroxy, mercapto, nitro, R_(A)R_(B)NS(O)₂— orR_(A)R_(B)N—;

R₂, R₃, and R₄ are independently hydrogen or halogen;

R₇ is hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkoxycarbonylalkyl, alkylsulfonyl, alkylthio, alkynyl,aryl, arylalkyl, aryloxy, arylthio, cyanoalkyl, cycloalkyl,cycloalkylalkyl, cycloalkyloxy, cycloalkylthio, haloalkoxy, haloalkyl,haloalkylsulfonyl, haloalkylthio, halogen, heteroaryl, heteroarylalkyl,heteroaryloxy, heteroarylthio, heterocycle, heterocyclealkyl, hydroxy,hydroxyalkyl, —R_(C)R_(D)N—, (R_(A)R_(B)N)carbonyl-,(R_(A)R_(B)N)sulfonyl-; or R_(A)S(O)₂;

R₆ and R₈ are independently hydrogen, lower alkenyl, lower alkoxy, loweralkyl, lower alkylthio, lower alkynyl, lower haloalkoxy, lowerhaloalkyl, lower haloalkylthio, halogen, hydroxy, mercapto, orR_(A)R_(B)N—;

alternatively, R₇ and R₆ taken together with the atoms they are attachedcan form a ring selected from the group consisting of2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxinyl;2,3-tetrahydro-benzo[1,4]dioxinyl; 2,2-difluoro-benzo[1,3]dioxolyl; and2,2-dihydro-benzo[1,3]dioxolyl;

R_(A) and R_(B) are independently alkyl, hydrogen, haloalkyl, orheterocycle;

R_(C) and R_(D) are independently hydrogen, alkenyl, alkoxycarbonyl,alkyl, alkylcarbonyl, alkynyl, or (R_(A)R_(B)N)carbonyl;

L is

— is absent or a single bond; and

R₁₁, R₁₂, R₁₃, and R₁₄ are independently hydrogen, alkoxy, alkyl, orhydroxy.

Also, the present invention is directed to compounds of general formula(III)

— is a single bond;

X₁ is CR₁;

X₂ is CR₂;

R₁ is hydrogen, lower haloalkyl or halogen;

R₂, R₃, R₄, and R₆, are hydrogen;

R₅ is alkyl, hydrogen, halogen, alkoxy, or haloalkoxy;

R₇ is alkoxy, alkyl, alkylthio, cycloalkyl, haloalkoxy, haloalkyl,haloalkylsulfonyl, haloalkylthio, halogen, R_(C)R_(D)N—; or R_(A)S(O)₂—;

R₁₁, R₁₂, R₁₃, and R₁₄ are hydrogen; and

R_(A), R_(C) and R_(D) are independently hydrogen or alkyl.

Also, the present invention is directed to compounds of general formula(VI)

wherein

X₁ is N or CR₁; X₅ is N or CR₅;

X₆ is a bond or CR₆;

X₇ is N or CR₇; X₈ is N or CR₈; X₉ is N or CR₉;

R₁, R₅, and R₉ are independently selected from the group consisting ofhydrogen, alkyl, alkoxy, halogen, haloalkyl and heterocycle;R₇ is hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkoxycarbonylalkyl, alkylsulfonyl, alkylthio, alkynyl,aryl, arylalkyl, aryloxy, arylthio, cyanoalkyl, cycloalkyl,cycloalkylalkyl, cycloalkyloxy, cycloalkylthio, haloalkoxy, haloalkyl,haloalkylsulfonyl, haloalkylthio, halogen, heteroaryl, heteroarylalkyl,heteroaryloxy, heteroarylthio, heterocycle, heterocyclealkyl, hydroxy,hydroxyalkyl, R_(C)R_(D)N—, (R_(A)R_(B)N)carbonyl-,(R_(A)R_(B)N)sulfonyl-; or R_(A)S(O)₂—;R₆ and R₈ are independently hydrogen, lower alkenyl, lower alkoxy, loweralkyl, lower alkylthio, lower alkynyl, lower haloalkoxy, lowerhaloalkyl, lower haloalkylthio, halogen, hydroxy, mercapto, orR_(A)R_(B)N—;R_(A) and R_(B) are independently alkyl, hydrogen, haloalkyl, orheterocycle; andR_(C) and R_(D) are independently hydrogen, alkenyl, alkoxycarbonyl,alkyl, alkylcarbonyl, alkynyl, or (NR_(A)R_(B))carbonyl.

DETAILED DESCRIPTION OF THE PRESENT INVENTION (1) Embodiments

In the principal embodiment, compounds of formula (I) are disclosed

or a pharmaceutically acceptable salt or prodrug thereof, wherein

A is

X₁ is N or CR₁;

X₂ is N or CR₂;

X₃ is O or N;

R is absent or O;

R₁ is hydrogen, lower alkoxy, lower alkenyl, lower alkyl, loweralkylthio, lower alkynyl, lower haloalkoxy, lower haloalkyl, lowerhaloalkylthio, halogen, hydroxy, mercapto, nitro, or R_(A)R_(B)NS(O)₂—or R_(A)R_(B)N—;

R₂, R₃, and R₄ are independently hydrogen or halogen;

R₇ is hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkxycarbonylalkyl, alkylsulfonyl, alkylthio, alkynyl,aryl, arylalkyl, aryloxy, arylthio, cyanoalkyl, cycloalkyl,cycloalkylalkyl, cycloalkyloxy, cycloalkylthio, haloalkoxy, haloalkyl,haloalkylsulfonyl, haloalkylthio, halogen, heteroaryl, heteroarylalkyl,heteroaryloxy, heteroarylthio, heterocycle, heterocyclealkyl, hydroxy,hydroxyalkyl, —R_(C)R_(D)N—, (R_(A)R_(B)N)carbonyl-,(R_(A)R_(B)N)sulfonyl-; or R_(A)S(O)₂—

R₆ and R₈ are independently hydrogen, lower alkenyl, lower alkoxy, loweralkyl, lower alkylthio, lower alkynyl, lower haloalkoxy, lowerhaloalkyl, lower haloalkylthio, halogen, hydroxy, mercapto, orR_(A)R_(B)N—;

alternatively, R₇ and R₆ taken together with the atoms they are attachedcan form a ring selected from the group consisting of2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxinyl;2,3-tetrahydro-benzo[1,4]dioxinyl; 2,2-difluoro-benzo[1,3]dioxolyl; and2,2-dihydro-benzo[1,3]dioxolyl;

R_(A) and R_(B) are independently alkyl, hydrogen, haloalkyl, orheterocycle;

R_(C) and R_(D) are independently hydrogen, alkenyl, alkoxycarbonyl,alkyl, alkylcarbonyl, alkynyl, or (R_(A)R_(B)N)carbonyl;

L is

— is absent or a single bond; and

R₁₁, R₁₂, R₁₃, and R₁₄ are independently hydrogen, alkoxy, alkyl, orhydroxy.

Another embodiment of the present invention relates to compounds offormula (II)

or a pharmaceutically acceptable salt or prodrug thereof wherein — isabsent or a single bond; X₁ is N or CR₁; X₂ is N or CR₂; R₁ is hydrogen,lower alkoxy, lower alkenyl, lower alkyl, lower alkylthio, loweralkynyl, lower haloalkoxy, lower haloalkyl, lower haloalkylthio,halogen, hydroxy, mercapto, nitro, or R_(A)R_(B)N—; R₂, R₃, and R₄ areindependently hydrogen or halogen; R₇ is hydrogen, alkenyl, alkoxy,alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl, alkylsulfonyl,alkylthio, alkynyl, aryl, arylalkyl, aryloxy, arylthio, cycloalkyl,cycloalkylalkyl, cycloalkyloxy, cycloalkylthio, haloalkoxy, haloalkyl,haloalkylsulfonyl, haloalkylthio, halogen, heteroaryl, heteroarylalkyl,heteroaryloxy, heteroarylthio, heterocycle, heterocyclealkyl, hydroxy,hydroxyalkyl, R_(C)R_(D)N, (R_(A)R_(B)N)carbonyl, or(R_(A)R_(B)N)sulfonyl; R₆ and R₈ are independently hydrogen, loweralkenyl, lower alkoxy, lower alkyl, lower alkylthio, lower alkynyl,lower haloalkoxy, lower haloalkyl, lower haloalkylthio, halogen,hydroxy, mercapto, or R_(A)R_(B)N—; R_(A) and R_(B) are independentlyhydrogen or alkyl; R_(C) and R_(D) are independently hydrogen, alkenyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, or (R_(A)R_(B)N)carbonyl;and R₁₁, R₁₂, R₁₃, and R₁₄ are independently hydrogen, alkoxy, alkyl, orhydroxy.

Another embodiment of the present invention relates to compounds offormula (II) wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; R₁ islower haloalkyl or halogen; R₂, R₃, and R₄ are hydrogen; R₇ is alkoxy,alkyl, alkylthio, alkylcarbonyl, hydroxyalkyl, alkylcarbonylalkyl,cycloalkyl, haloalkoxy, haloalkyl, haloalkylsulfonyl, haloalkylthio,halogen, R_(C)R_(D)N—; or R_(A)S(O)₂—; R₁₁, R₁₂, R₁₃, and R₁₄ arehydrogen; R_(C) and R_(D) are independently hydrogen or alkyl; and R₆and R₈ are as defined in formula (II).

Another embodiment of the present invention relates to compounds offormula (II) wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; R₁ islower haloalkyl or halogen wherein the halogen or haloalkyl is —Cl ortrifluoromethyl; R₂, R₃, and R₄ are hydrogen; R₆ is hydrogen, loweralkyl, lower haloalkyl, or halogen; R₇ is alkoxy, alkyl, alkylthio,haloalkoxy, haloalkylsulfonyl, haloalkyl, haloalkylthio, halogen, orR_(C)R_(D)N—; R₈, R₁₁, R₁₂, R₁₃, and R₁₄ are hydrogen; and R_(C) andR_(D) are independently hydrogen or alkyl.

Another embodiment of the present invention relates to compounds offormula (II) wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; R₁ islower haloalkyl or halogen wherein the halogen or haloalkyl is —Cl ortrifluoromethyl; R₂, R₃, and R₄ are hydrogen; R₇ is halogen wherein thehalogen is —Cl; and R₆, R₈, R₁₁, R₁₂, R₁₃, and R₁₄ are hydrogen.

Another embodiment of the present invention relates to compounds offormula (II) wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; R₁ islower haloalkyl or halogen; R₂, R₃, and R₄ are hydrogen; R₇ is aryl oraryloxy; R₁₁, R₁₂, R₁₃, and R₁₄ are hydrogen; and R₆, and R₈ are asdefined in formula (II).

Another embodiment of the present invention relates to compounds offormula (II) wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; R₁ islower haloalkyl or halogen wherein the halogen or haloalkyl is —Cl ortrifluoromethyl; R₂, R₃, and R₄ are hydrogen; R₆ is hydrogen, loweralkyl, lower haloalkyl, or halogen; R₇ is aryl wherein the aryl isphenyl; and R₈, R₁₁, R₁₂, R₁₃, and R₁₄ are hydrogen.

Another embodiment of the present invention relates to compounds offormula (II) wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; R₁ islower haloalkyl or halogen wherein the halogen or haloalkyl is —Cl ortrifluoromethyl; R₂, R₃, and R₄ are hydrogen; R₆ is hydrogen, loweralkyl, lower haloalkyl, or halogen; R₇ is aryloxy wherein the aryl ofthe aryloxy is phenyl; and R₈, R₁₁, R₁₂, R₁₃, and R₁₄ are hydrogen.

Another embodiment of the present invention relates to compounds offormula (II) wherein wherein — is a single bond; X₁ is CR₁; X₂ is CR₂;R₁ is lower haloalkyl or halogen; R₂, R₃, and R₄ are hydrogen; R₇ isheterocycle; R₁₁, R₁₂, R₁₃, and R₁₄ are hydrogen; and R₆, and R₈ are asdefined in formula (II).

Another embodiment of the present invention relates to compounds offormula (II) wherein wherein — is a single bond; X₁ is CR₁; X₂ is CR₂;R₁ is lower haloalkyl or halogen wherein the halogen or haloalkyl is —Clor trifluoromethyl; R₂, R₃, and R₄ are hydrogen; R₆ is hydrogen, loweralkyl, lower haloalkyl, or halogen; R₇ is heterocycle wherein theheterocycle is azepanyl, morpholinyl, or piperidinyl; and R₈, R₁₁, R₁₂,R₁₃, and R₁₄ are hydrogen.

Another embodiment of the present invention relates to compounds offormula (II) in which R₇ and R₆ taken together with the atoms they areattached can form a ring selected from the group consisting of2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxinyl;2,3-tetrahydro-benzo[1,4]dioxinyl; 2,2-difluoro-benzo[1,3]dioxolyl; and2,2-dihydro-benzo[1,3]dioxolyl. Preferred embodiments include compoundsin which R₇ and R₆ taken together with the atoms they are attached canform 2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxinyl and2,2-difluoro-benzo[1,3]dioxolyl.

Another embodiment of the present invention relates to compounds offormula (II) wherein — is a single bond; X₁ is CR₁; X₂ is CR₂; R₁ islower haloalkyl or halogen wherein the halogen or haloalkyl is —Cl ortrifluoromethyl; R₂, R₃, and R₄ are hydrogen; R₆ is lower alkyl, lowerhaloalkyl, or halogen; and R₇, R₈, R₁₁, R₁₂, R₁₃, and R₁₄ are hydrogen.

Another embodiment of the present invention relates to compounds offormula (II) wherein wherein — is a single bond; X₁ is CR₁; X₂ is CR₂;R₁ is lower haloalkyl or halogen wherein the halogen or haloalkyl is —Clor trifluoromethyl; R₂, R₃, and R₄ are hydrogen; R₆ is lower alkyl,lower haloalkyl, or halogen; and R₇, R₈, R₁₁, R₁₂, R₁₃, and R₁₄ arehydrogen.

Another embodiment of the present invention relates to compounds offormula (II) wherein — is a single bond; X₁ is N; X₂ is CR₂; R₂, R₃, andR₄ are hydrogen; R₇ is alkoxy, alkyl, alkylthio, haloalkoxy, haloalkyl,haloalkylsulfonyl, haloalkylthio, halogen, or R_(C)R_(D)N—; R₁₁, R₁₂,R₁₃, and R₁₄ are hydrogen; R_(C) and R_(D) are independently hydrogen oralkyl; and R₆ and R₈ are as defined in formula (II).

Another embodiment of the present invention relates to compounds offormula (II) wherein — is a single bond; X₁ is N; X₂ is CR₂; R₂, R₃, R₄,and R₈ are hydrogen; R₆ is hydrogen, lower alkyl, lower haloalkyl, orhalogen; R₇ is alkoxy, alkyl, alkylthio, haloalkoxy, haloalkyl,haloalkylsulfonyl, haloalkylthio, halogen, or R_(C)R_(D)N—; R₁₁, R₁₂,R₁₃, and R₁₄ are hydrogen; and R_(C) and R_(D) are independentlyhydrogen or alkyl.

Another embodiment of the present invention relates to compounds offormula (II) wherein — is a single bond; X₁ is N; X₂ is CR₂; R₂, R₃, andR₄ are hydrogen; R₇ is heterocycle; R₁₁, R₁₂, R₁₃, and R₁₄ are hydrogen;R_(C) and R_(D) are independently hydrogen or alkyl; and R₆ and R₈ areas defined in formula (II).

Another embodiment of the present invention relates to compounds offormula (III)

or a pharmaceutically acceptable salt or prodrug thereof, in which — isa single bond; X₁ is CR₁; X₂ is CR₂; R₁ is hydrogen, lower haloalkyl orhalogen; R₂, R₃, R₄, and R₆, are hydrogen; R₅ is alkyl, hydrogen,halogen, alkoxy, or haloalkoxy; R₇ is alkoxy, alkyl, alkylthio,cycloalkyl, haloalkoxy, haloalkyl, haloalkylsulfonyl, haloalkylthio,halogen, R_(C)R_(D)N—; or R_(A)S(O)₂—; R₁₁, R₁₂, R₁₃, and R₁₄ arehydrogen; and R_(A), R_(C) and R_(D) are independently hydrogen oralkyl.

Another embodiment of the present invention relates to compounds offormula (IV)

or a pharmaceutically acceptable salt or prodrug thereof wherein X₁ is Nor CR₁; X₂ is N or CR₂; R₁ is hydrogen, lower alkoxy, lower alkenyl,lower alkyl, lower alkylthio, lower alkynyl, lower haloalkoxy, lowerhaloalkyl, lower haloalkylthio, halogen, hydroxy, mercapto, nitro, orR_(A)R_(B)N—; R₂, R₃, and R₄ are independently hydrogen or halogen; R₇is hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylsulfonyl, alkylthio, alkynyl, aryl, arylalkyl,aryloxy, arylthio, cycloalkyl, cycloalkylalkyl, cycloalkyloxy,cycloalkylthio, haloalkoxy, haloalkyl, haloalkylsulfonyl, haloalkylthio,halogen, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio,heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, R_(C)R_(D)N—,(R_(A)R_(B)N)carbonyl-, or (R_(A)R_(B)N)sulfonyl-; R₆ and R₈ areindependently hydrogen, lower alkenyl, lower alkoxy, lower alkyl, loweralkylthio, lower alkynyl, lower haloalkoxy, lower haloalkyl, lowerhaloalkylthio, halogen, hydroxy, mercapto, or R_(A)R_(B)N—; R_(A) andR_(B) are independently hydrogen or alkyl; and R_(C) and R_(D) areindependently hydrogen, alkenyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkynyl, or (R_(A)R_(B)N)carbonyl-.

Another embodiment of the present invention relates to compounds offormula (IV) wherein X₁ is CR₁; X₂ is CR₂; R₁ is lower haloalkyl orhalogen; R₂, R₃, and R₄ are hydrogen; R₇ is alkoxy, alkyl, alkylthio,haloalkoxy, haloalkyl, haloalkylthio, halogen, or R_(C)R_(D)N—; R₁₁,R₁₂, R₁₃, and R₁₄ are hydrogen; R_(C) and R_(D) are independentlyhydrogen or alkyl; and R₆ and R₈ are as defined in formula (IV).

Another embodiment of the present invention relates to compounds offormula (IV) wherein X₁ is CR₁; X₂ is CR₂; R₁ is lower haloalkyl orhalogen wherein the halogen or haloalkyl is —Cl or trifluoromethyl; R₂,R₃, and R₄ are hydrogen; R₆ is hydrogen, lower alkyl, lower haloalkyl,or halogen; R₇ is alkoxy, alkyl, alkylthio, haloalkoxy, haloalkyl,haloalkylthio, halogen, or R_(C)R_(D)N—; R₈, R₁₁, R₁₂, R₁₃, and R₁₄ arehydrogen; and R_(C) and R_(D) are independently hydrogen or alkyl.

Another embodiment of the present invention relates to compounds offormula (V)

or a pharmaceutically acceptable salt or prodrug wherein X₁ is N or CR₁;X₂ is N or CR₂; R₁ is hydrogen, lower alkoxy, lower alkenyl, loweralkyl, lower alkylthio, lower alkynyl, lower haloalkoxy, lowerhaloalkyl, lower haloalkylthio, halogen, hydroxy, mercapto, nitro, orR_(A)R_(B)N—; R₂, R₃, and R₄ are independently hydrogen or halogen; R₇is hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylsulfonyl, alkylthio, alkynyl, aryl, arylalkyl,aryloxy, arylthio, cycloalkyl, cycloalkylalkyl, cycloalkyloxy,cycloalkylthio, haloalkoxy, haloalkyl, haloalkylsulfonyl, haloalkylthio,halogen, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio,heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, R_(C)R_(D)N—,(R_(A)R_(B)N)carbonyl-, or (R_(A)R_(B)N)sulfonyl-; R₆ and R₈ areindependently hydrogen, lower alkenyl, lower alkoxy, lower alkyl, loweralkylthio, lower alkynyl, lower haloalkoxy, lower haloalkyl, lowerhaloalkylthio, halogen, hydroxy, mercapto, or R_(A)R_(B)N—; R_(A) andR_(B) are independently hydrogen or alkyl; and R_(C) and R_(D) areindependently hydrogen, alkenyl, alkoxycarbonyl, alkyl, alkylcarbonyl,alkynyl, or (R_(A)R_(B)N)carbonyl-.

Another embodiment of the present invention relates to compounds offormula (IV) wherein X₁ is CR₁; X₂ is CR₂; R₁ is lower haloalkyl orhalogen wherein the halogen or haloalkyl is —Cl or trifluoromethyl; R₂,R₃, and R₄ are hydrogen; R₇ is alkoxy, alkyl, alkylthio, haloalkoxy,haloalkyl, haloalkylthio, halogen, or R_(C)R_(D)N—; R₆, R₈, R₁₁, R₁₂,R₁₃, and R₁₄ are hydrogen; and R_(C) and R_(D) are independentlyhydrogen or alkyl.

Another embodiment of the present invention relates to compounds offormula (VI)

or a pharmaceutically acceptable salt or prodrug wherein X₃ is S; R₂,and R₃ are independently hydrogen or halogen; R₇ is hydrogen, alkenyl,alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl,alkoxycarbonylalkyl, alkylsulfonyl, alkylthio, alkynyl, aryl, arylalkyl,aryloxy, arylthio, cyanoalkyl, cycloalkyl, cycloalkylalkyl,cycloalkyloxy, cycloalkylthio, haloalkoxy, haloalkyl, haloalkylsulfonyl,haloalkylthio, halogen, heteroaryl, heteroarylalkyl, heteroaryloxy,heteroarylthio, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl,R_(C)R_(D)N—, (R_(A)R_(B)N)carbonyl-, (R_(A)R_(B)N)sulfonyl-; orR_(A)S(O)₂—; R₆ and R₈ are independently hydrogen, lower alkenyl, loweralkoxy, lower alkyl, lower alkylthio, lower alkynyl, lower haloalkoxy,lower haloalkyl, lower haloalkylthio, halogen, hydroxy, mercapto, orR_(A)R_(B)N—; and R_(A) and R_(B) are independently alkyl, hydrogen,haloalkyl, or heterocycle.

Another embodiment of the present invention relates to compounds offormula (VII)

or a pharmaceutically acceptable salt or prodrug wherein X₁ is N or CR₁;X₅ is N or CR₅; X₆ is a bond or CR₆; X₇ is N or CR₇; X₈ is N or CR₈; X₉is N or CR₉; R₁, R₅, and R₉ are independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, halogen, haloalkyl andheterocycle; R₇ is hydrogen, alkenyl, alkoxy, alkoxycarbonyl,alkoxysulfonyl, alkyl, alkylcarbonyl, alkoxycarbonylalkyl,alkylsulfonyl, alkylthio, alkynyl, aryl, arylalkyl, aryloxy, arylthio,cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, cycloalkylthio,haloalkoxy, haloalkyl, haloalkylsulfonyl, haloalkylthio, halogen,heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, heterocycle,heterocyclealkyl, hydroxy, hydroxyalkyl, R_(C)R_(D)N—,(R_(A)R_(B)N)carbonyl-, (R_(A)R_(B)N)sulfonyl-; or R_(A)S(O)₂—; R₆ andR₈ are independently hydrogen, lower alkenyl, lower alkoxy, lower alkyl,lower alkylthio, lower alkynyl, lower haloalkoxy, lower haloalkyl, lowerhaloalkylthio, halogen, hydroxy, mercapto, or R_(A)R_(B)N—;R_(A) and R_(B) are independently alkyl, hydrogen, haloalkyl, orheterocycle; andR_(C) and R_(D) are independently hydrogen, alkenyl, alkoxycarbonyl,alkyl, alkylcarbonyl, alkynyl, or (R_(A)R_(B)N)carbonyl-.

Another embodiment of the present invention relates to compounds offormula (VII) wherein X₁ is CR₁; X₅ is CR₅; X₆ is CR₆; X₇ is CR₇; X₈ isCR₈; X₉ is N or CR₉; R₇ and R₈ are independently selected from the groupconsisting of hydrogen, alkyl, and halogen.

Another embodiment of the present invention relates to compounds offormula (VII) wherein X₁ is CR₁; X₅ is CR₅; X₆ is CR₆; X₇ is CR₇; X₈ isN; X₉ is CR₉; R₅, R₆, R₉ and R₁, are independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, and halogen; R₇ ishydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkoxycarbonylalkyl, alkylsulfonyl, alkylthio, alkynyl,aryl, arylalkyl, aryloxy, arylthio, cyanoalkyl, cycloalkyl,cycloalkylalkyl, cycloalkyloxy, cycloalkylthio, haloalkoxy, haloalkyl,haloalkylsulfonyl, haloalkylthio, halogen, heteroaryl, heteroarylalkyl,heteroaryloxy, heteroarylthio, heterocycle, heterocyclealkyl, hydroxy,hydroxyalkyl, R_(C)R_(D)N—, (R_(A)R_(B)N)carbonyl-,(R_(A)R_(B)N)sulfonyl-; or R_(A)S(O)₂—; R_(A) and R_(B) areindependently alkyl, hydrogen, halogen, haloalkyl, or heterocycle; andR_(C) and R_(D) are independently hydrogen, alkenyl, alkoxycarbonyl,alkyl, alkylcarbonyl, alkynyl, or (R_(A)R_(B)N)carbonyl.

Another embodiment of the present invention relates to compounds offormula (VII) wherein X₁ is CR₁; X₅ is CR₅; X₆ is a bond; X₇ is N; X₈ isN; X₉ is CR₉; R₁, R₉ and R₅, are independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, and halogen.

Another embodiment of the present invention relates to compounds offormula (VII) wherein X₁ is N; X₅ is CR₅; X₆ is CR₆; X₇ is CR₇; X₈ is N;X₉ is CR₉; R₆, R₇, R₉ and R₅, are independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, and halogen.

Another embodiment of the present invention relates to pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof formula (I-VII) or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to a method fortreating pain in a mammal, comprising administering a therapeuticallyeffective amount of a compound of formula (I-VII) or a pharmaceuticallyacceptable salt thereof.

(2) Definition of Terms

As used throughout this specification and the appended claims, thefollowing terms have the following meanings:

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkoxycarbonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkoxysulfonyl” as used herein, means an alkoxy group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkoxysulfonyl include, but are not limited to, methoxysulfonyl,ethoxysulfonyl and propoxysulfonyl.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylcarbonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “alkylcarbonyloxy” as used herein, means an alkylcarbonylgroup, as defined herein, appended to the parent molecular moietythrough an oxygen atom. Representative examples of alkylcarbonyloxyinclude, but are not limited to, acetyloxy, ethylcarbonyloxy, andtert-butylcarbonyloxy.

The term “alkylsulfonyl” as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group, as defined herein. Representative examples ofalkylsulfonyl include, but are not limited to, methylsulfonyl andethylsulfonyl.

The term “alkylthio” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of alkylthio include, but are not limited,methylthio, ethylthio, tert-butylthio, and hexylthio.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, and 1-butynyl.

The term “aryl” as used herein, means a monocyclic-ring system, abicyclic-fused ring system, or a tricyclic-fused ring system wherein oneor more of the fused rings are aromatic. Representative examples of arylinclude, but are not limited to, anthracenyl, azulenyl, fluorenyl,2,3-dihydroindenyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.

The aryl groups of this invention can be optionally substituted with 1,2, 3, or 4 substituents independently selected from alkenyl, alkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl,alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, carboxy, cyano,formyl, haloalkoxy, haloalkyl, haloalkylsulfonyl, haloalkylthio,halogen, hydroxy, hydroxyalkyl, mercapto, nitro, R_(A)R_(B)N—,(R_(A)R_(B)N)carbonyl-, and (R_(A)R_(B)N)sulfonyl-.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “aryloxy” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of aryloxy include, but are not limited to,phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy,and 3,5-dimethoxyphenoxy.

The term “arylthio” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through a sulfur atom.Representative examples of arylthio include, but are not limited to,phenylthio and 2-naphthylthio.

The term “carbonyl” as used herein, means a —C(O)— group.

The term “carboxy” as used herein, means a —CO₂H group.

The term “cyano” as used herein, means a —CN group.

The term “cycloalkyl” as used herein, means a saturated cyclichydrocarbon group containing from 3 to 8 carbons. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl.

The cycloalkyl groups of the present invention are optionallysubstituted with 1, 2, 3, or 4 substituents selected from alkenyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,carboxy, cyano, formyl, haloalkoxy, haloalkyl, haloalkylsulfonyl,haloalkylthio, halogen, hydroxy, hydroxyalkyl, mercapto, R_(A)R_(B)N—,(R_(A)R_(B)N)carbonyl-, and (R_(A)R_(B)N)sulfonyl-.

The term “cycloalkylalkyl” as used herein, means a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of cycloalkylalkylinclude, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl,cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl.

The term “cycloalkyloxy” as used herein, means cycloalkyl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom, as defined herein. Representative examples of cycloalkyloxyinclude, but are not limited to, cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

The term “cycloalkylthio” as used herein, means cycloalkyl group, asdefined herein, appended to the parent molecular moiety through a sulfuratom, as defined herein. Representative examples of cycloalkylthioinclude, but are not limited to, cyclopropylthio, cyclobutylthio,cyclopentylthio, cyclohexylthio, cycloheptylthio, and cyclooctylthio.

The term “formyl” as used herein, means a —C(O)H group.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through analkoxy group, as defined herein. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, and pentafluoroethoxy.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “haloalkylsulfonyl” as used herein, means a haloalkyl group, asdefined herein, appended to the parent molecular moiety through asulfonyl group. Representative examples of haloalkylsulfonyl include,but are not limited to, trifluoromethylsulfonyl and(pentafluoroethyl)sulfonyl.

The term “haloalkylthio” as used herein, means a haloalkyl group, asdefined herein, appended to the parent molecular moiety through a sulfuratom. Representative examples of haloalkylthio include, but are notlimited to, trifluoromethylthio and (pentafluoroethyl)thio.

The term “heteroaryl,” as used herein, refers to an aromatic five- orsix-membered ring wherein 1, 2, 3, or 4 heteroatoms are independentlyselected from N, O, or S. The five membered rings have two double bondsand the six membered rings have three double bonds. The heteroarylgroups are connected to the parent molecular moiety through a carbon ornitrogen atom. Representative examples of heteroaryl include, but arenot limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, pyrrolyl, tetraazolyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, and triazinyl.

The heteroaryl groups of the present invention are optionallysubstituted 1, 2, 3, or 4 substituents independently selected fromalkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,carboxy, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen,hydroxy, hydroxyalkyl, mercapto, nitro, R_(A)R_(B)N—,(R_(A)R_(B)N)carbonyl-, and (R_(A)R_(B)N)sulfonyl.

The term “heteroarylalkyl” as used herein, means a heteroaryl, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of heteroarylalkylinclude, but are not limited to, pyridin-3-ylmethyl and2-pyrimidin-2-ylpropyl.

The term “heteroaryloxy” as used herein, means a heteroaryl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom. Representative examples of heteroaryloxy include, but arenot limited to, pyridin-3-yloxy, pyridin-4-yloxy, and quinolin-3-yloxy.

The term “heteroarylthio” as used herein, means a heteroaryl group, asdefined herein, appended to the parent molecular moiety through a sulfuratom. Representative examples of heteroarylthio include, but are notlimited to, pyridin-3-ylthio, pyridin-4-ylthio, and quinolin-3-ylthio.

The term “heterocycle,” as used herein, refers to a three, four, five,six, seven or eight membered ring containing one or two heteroatomsindependently selected from the group consisting of nitrogen, oxygen,and sulfur. The three membered ring has zero double bonds. The four andfive membered ring has zero or one double bond. The six membered ringhas zero, one, or two double bonds. The seven and eight membered ringshave zero, one, two, or three double bonds. The heterocycle groups ofthe present invention can be attached to the parent molecular moietythrough a carbon atom or a nitrogen atom. The heterocycle groups of thepresent invention can be a monocyclic-ring system, a bicyclic-fused ringsystem, or a tricyclic-fused ring system. Representative examples ofheterocycle include, but are not limited to, azabycyclooctyl,azetidinyl, azepanyl, aziridinyl, azocanyl, morpholinyl, piperazinyl,piperidinyl, pyrrolidinyl, and thiomorpholinyl.

The heterocycles of the present invention are optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from alkenyl,alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxysulfonyl, alkyl,alkylcarbonyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl,carboxy, cyano, formyl, haloalkoxy, haloalkyl, haloalkylthio, halogen,hydroxy, hydroxyalkyl, mercapto, R_(A)R_(B)N, (R_(A)R_(B)N)carbonyl, and(R_(A)R_(B)N)sulfonyl.

The term “heterocyclealkyl” as used herein, means a heterocycle, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of heterocyclealkylinclude, but are not limited to, piperidin-1-ylmethyl and2-piperidin-1-ylethyl.

The term “hydroxy” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “lower alkenyl” as used herein, is a subset of alkenyl, asdefined herein, and means an alkenyl group containing from 2 to 4 carbonatoms. Examples of lower alkenyl are ethenyl, propenyl, and butenyl.

The term “lower alkoxy” as used herein, is a subset of alkoxy, asdefined herein, and means a lower alkyl group, as defined herein,appended to the parent molecular moiety through an oxygen atom, asdefined herein. Representative examples of lower alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, andtert-butoxy.

The term “lower alkyl” as used herein, is a subset of alkyl, as definedherein, and means a straight or branched chain hydrocarbon groupcontaining from 1 to 4 carbon atoms. Representative examples of loweralkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, and tert-butyl.

The term “lower alkylthio” as used herein, is a subset of alkylthio, andmeans a lower alkyl group, as defined herein, appended to the parentmolecular moiety through a sulfur atom. Representative examples of loweralkylthio include, but are not limited, methylthio, ethylthio, andtert-butylthio.

The term “lower alkynyl” as used herein, is a subset of alkynyl, asdefined herein, and means an alkynyl group containing from 2 to 4 carbonatoms. Examples of lower alkynyl are ethynyl, propynyl, and butynyl.

The term “lower haloalkoxy” as used herein, is a subset of haloalkoxy,as defined herein, and means a straight or branched chain haloalkoxygroup containing from 1 to 4 carbon atoms. Representative examples oflower haloalkoxy include, but are not limited to, trifluoromethoxy,trichloromethoxy, dichloromethoxy, fluoromethoxy, and pentafluoroethoxy.

The term “lower haloalkyl” as used herein, is a subset of haloalkyl, asdefined herein, and means a straight or branched chain haloalkyl groupcontaining from 1 to 4 carbon atoms. Representative examples of lowerhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, dichloromethyl, fluoromethyl, and pentafluoroethyl.

The term “lower haloalkylthio” as used herein, is a subset ofhaloalkylthio, as defined herein, and means a straight or branched chainhaloalkylthio group containing from 1 to 4 carbon atoms. Representativeexamples of lower haloalkylthio include, but are not limited to,trifluoromethylthio, trichloromethylthio, fluoromethylthio, and(pentafluoroethyl)thio.

The term “mercapto” as used herein, means a —SH group.

The term “nitro” as used herein, means a —NO₂ group.

The term “R_(A)R_(B)N-” as used herein, means two groups, R_(A) andR_(B), which are appended to the parent molecular moiety through anitrogen atom. R_(A) and R_(B) are each independently hydrogen or alkyl.Representative examples of R_(A)R_(B)N include, but are not limited to,amino, methylamino, dimethylamino, and diethylamino.

The term “(R_(A)R_(B)N)carbonyl” as used herein, means a R_(A)R_(B)N—group, as defined herein, appended to the parent molecular moietythrough a carbonyl group, as defined herein. Representative examples of(R_(A)R_(B)N)carbonyl include, but are not limited to, aminocarbonyl,(methylamino)carbonyl, (dimethylamino)carbonyl, and(ethylmethylamino)carbonyl.

The term “(R_(A)R_(B)N)sulfonyl” as used herein, means a R_(A)R_(B)N—group, as defined herein, appended to the parent molecular moietythrough a sulfonyl group, as defined herein. Representative examples of(R_(A)R_(B)N)sulfonyl include, but are not limited to, aminosulfonyl,(methylamino)sulfonyl, (dimethylamino)sulfonyl, and(ethylmethylamino)sulfonyl.

The term “R_(C)R_(D)N-” as used herein, means two groups, R_(C) andR_(D), which are appended to the parent molecular moiety through anitrogen atom. R_(C) and R_(D) are each independently hydrogen, alkenyl,alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, or(R_(A)R_(B)N)carbonyl. Representative examples of R_(C)R_(D)N include,but are not limited to, amino, methylamino, dimethylamino, andethylmethylamino.

The term “sulfonyl” as used herein, means a —S(O)₂— group.

Compounds of the present invention can exist as stereoisomers, whereinasymmetric or chiral centers are present. Stereoisomers are designated(R) or (S), depending on the configuration of substituents around thechiral carbon atom. The terms (R) and (S) used herein are configurationsas defined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., (1976), 45: 13-30. The presentinvention contemplates various stereoisomers and mixtures thereof andare specifically included within the scope of this invention.Stereoisomers include enantiomers, diastereomers, and mixtures ofenantiomers or diastereomers. Individual stereoisomers of compounds ofthe present invention may be prepared synthetically from commerciallyavailable starting materials which contain asymmetric or chiral centersor by preparation of racemic mixtures followed by resolution, atechnique well-known to those of ordinary skill in the art. Thesemethods of resolution are exemplified by (1) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography and liberationof the optically pure product from the auxiliary, (2) direct separationof the mixture of optical enantiomers on chiral chromatographic columns,or (3) formation of a diastereomeric salt followed by selectiverecrystallization of one of the diastereomeric salts.

Compounds of the present invention were named by ACD/ChemSketch version5.0 (developed by Advanced Chemistry Development, Inc., Toronto, ON,Canada) or were given names consistent with ACD nomenclature.

(3) Abbreviations

Abbreviations which have been used in the descriptions of the Schemesand the Examples that follow are: Ac for acetyl; Bu for butyl; DCC for1,3-dicyclohexylcarbodiimide; DIEA for diisopropylethylamine; DMAP for4-dimethylaminopyridine; DME for 1,2-dimethoxyethane; DMF forN,N-dimethylformamide; DMSO for dimethylsulfoxide; EDCI or EDC for1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride; Ph forphenyl; TFA for trifluoroacetic acid; THF for tetrahydrofuran; and Tffor —S(O)₂CF₃.

(4) Schemes and Examples

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic Schemes andExamples, which illustrate a means by which the compounds of the presentinvention can be prepared. Further, all citations herein areincorporated by reference.

4(a) Preparation of Compounds of the Present Invention

Amides of general formula (4), wherein X₁, X₂, X₃, R₃, R₄, R₆, R₇, andR₈ are as defined in formula (I-IV), can be prepared as described inScheme 1. 1,2,3,6-Tetrahydropyridine-4-carboxylic acid, prepared asdescribed in Examples 1A-1C herein, can be treated with 2-halo compoundsof general formula (1) and a base including, but not limited topotassium carbonate, in a solvent including, but not limited to, DMSO orDMF and heated until reaction is complete to provide acids of generalformula (2). Acids of general formula (2) can be coupled to anilines ofgeneral formula (3) using EDCI or DCC to provide amides of generalformula (4).

Amides of general formula (6) and general formula (8), wherein X₃, R₁,R₂, R₃, R₆, R₇, and R₈ are as defined in formula (I-IV), can be preparedas described in Scheme 1. Oxazoles or thiazoles of general formula (5)or general formula (7) can be processed in a similar manner as compoundsof general formula (1) in Scheme 1 to provide amides of general formula(6) or amides of general formula (8) both of which are representative ofthe compounds of the present invention.

Amides of general formula (12), wherein X₁, X₂, X₃, R₃, R₄, R₆, R₇, andR₈ are as defined in formula (I-IV), can be prepared as described inScheme 2. tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate,prepared as described in Examples 23A-23I herein, can be treated with2-halo compounds of general formula (1) as described in Scheme 1 toprovide compounds of general formula (9). Compounds of general formula(9) can be deprotected with trifluoroacetic acid in methylene chloride(1:1) or with 4.5N hydrochloric acid in 1,4-dioxane to provide compoundsof general formula (10). Compounds of general formula (10) can betreated with isocyanates of general formula (11) to provide amides ofgeneral formula (12), which are representative of compounds of thepresent invention.

Amides of general formula (13) and amides of general formula (14),wherein X₃, R₁, R₂, R₃, R₆, R₇, and R₈ are as defined in formula (I-IV),can be prepared as described in Scheme 2. Oxazoles or thiazoles ofgeneral formula (5) or general formula (7) can be processed in a similarmanner as compounds of general formula (1) in Scheme 2 to provide amidesof general formula (13) or amides of general formula (14) which are bothrepresentative of compounds of the present invention.

Amides of general formula (17), wherein X₁, X₂, X₃, R₃, R₄, R₆, R₇, andR₈ are as defined in formula (I-IV), can be prepared as described inScheme 3. 8-Benzyl-3,8-diazabicyclo[3.2.1]octane, prepared as describedin Examples 23A-23F herein, can be processed as described in Examples34A-34C to provide tert-butyl3,8-diazabicyclo[3.2.1]octane-3-carboxylate. tert-Butyl3,8-diazabicyclo[3.2.1]octane-3-carboxylate can be treated with 2-halocompounds of general formula (1) as described in Scheme 1 to providecompounds of general formula (15). Compounds of general formula (15) canbe deprotected with trifluoroacetic acid in methylene chloride (1:1) orwith 4.5N hydrochloric acid in 1,4-dioxane to provide compounds ofgeneral formula (16). Compounds of general formula (16) can be treatedwith isocyanates of general formula (11) to provide amides of generalformula (17) which are representative of compounds of the presentinvention.

Amides of general formula (18) and amides of general formula (19),wherein X₃, R₁, R₂, R₃, R₆, R₇, and R₈ are as defined in formula (I-IV),can be prepared as described in Scheme 3. Oxazoles or thiazoles ofgeneral formula (5) or general formula (7) can be processed in a similarmanner as compounds of general formula (1) in Scheme 3 to provide amidesof general formula (18) or amides of general formula (19) which arerepresentative of compounds of the present invention.

Amines of formula (20) when treated with chloropyridines of formula(21), wherein R₁ is lower haloalkyl or halogen, in the presence ofpotassium carbonate in DMSO will provide compounds of formula (22).Compounds of formula (22) when treated with hydrochloric acid willprovide compounds of formula (23). Compounds of formula (23) whentreated with lithium diisopropylamine andN-phenyltrifluoromethanesulfonimide will provide compounds of formula(24). Compounds of formula (24) when treated with PdCl₂(PPh₃)₂, carbondioxide, triethylamine in methanol will provide compounds of formula(25). Compounds of formula (25) when treated with sodium hydroxide orlithium hydroxide in alcoholic solvents will provide compounds offormula (26). Compounds of formula (26) when treated with anilines offormula (3) and EDCI will provide compounds of formula (27).Alternatively, compounds of formula (26) when treated with oxalylchloride followed by treatment with an aniline of formula (3) whereinR₈, R₇, and R₆ are defined in formula I-IV and a base such astriethylamine will provide compounds of formula (27). The preparation ofcompounds of formula (27) wherein R₁ is lower haloalkyl or halogen,particularly trifluoromethane or chloride are representative ofcompounds of the present invention.

Compounds of formula (28) and compounds of formula (29) when treatedwith potassium carbonate in DMSO will provide compounds of formula (30).Compounds of formula (30) when treated with compounds of formula (3)wherein R₈, R₇, and R₆ are as defined in formula (I-IV) and EDCI willprovide compounds of formula (32) which are representative of thecompounds of the present invention.

4(b) Examples Example 1N-(4-tert-butylphenyl)-3′-chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamideExample 1A 1-(1-chloroethyl) 4-ethyl3,6-dihydro-1,4(2H)-pyridinedicarboxylate

Ethyl 1-methyl-1,2,3,6-tetrahydro-4-pyridinecarboxylate (47 g, 278 mmol)in dichloroethane (800 mL) was treated with α-chloroethyl chloroformate(50 g, 350 mmol) dropwise at 0° C. The mixture was warmed to roomtemperature, refluxed for 2 hours, and then allowed to cool to roomtemperature. The mixture was concentrated under reduced pressure and theresidue was purified via column chromatography (SiO₂, ethyl acetate) toprovide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 6.88 (m, 1H), 6.61(q, 1H), 4.22 (q, 2H), 4.16 (m, 2H), 7.35 (d, 2H), 3.58 (m, 2H), 2.44(m, 2H), 1.82 (d, 3H), 1.30 (t, 3H).

Example 1B ethyl 1,2,3,6-tetrahydro-4-pyridinecarboxylate

1-(1-Chloroethyl) 4-ethyl 3,6-dihydro-1,4(2H)-pyridinedicarboxylate(61.8 g, 236 mmol) in methanol (500 mL) was heated at reflux for 30minutes. The mixture was allowed to cool to room temperature andconcentrated to provide the title compound. ¹H NMR (300 MHz, CDCl₃) δ6.86 (m, 1H), 4.22 (q, 2H), 3.85 (m, 2H), 3.34 (m, 2H), 2.75 (m, 2H),1.30 (t, 3H).

Example 1C 1,2,3,6-tetrahydropyridine-4-carboxylic acid

Ethyl 1,2,3,6-tetrahydro-4-pyridinecarboxylate (44.7 g, 234 mmol) indichloromethane (200 mL) was treated with aqueous K₂CO₃ (saturated) andthe phases were separated. The aqueous layer was dried under reducedpressure and the residue was triturated with dichloromethane (100×3 mL)and dissolved in methanol (100 mL). The solution was treated with asaturated solution of NaOH (10 g, 250 mmol) in methanol (250 mL) andsodium methoxide in methanol (0.5M, 200 mL, 100 mmol). After stirring atroom temperature for two days, the mixture was concentrated underreduced pressure. The residue was triturated with methanol (200×5 mL)and dried under reduced pressure to provide the title compound. ¹H NMR(300 MHz, CD₃OD) δ 6.60 (m, 1H), 3.38 (m, 2H), 2.88 (m, 2H), 2.30 (m,2H).

Example 1D 3′-chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylic acid

1,2,3,6-Tetrahydro-4-pyridinecarboxylic acid (7.0 g, 47 mmol) and2-bromo-3-chloropyridine (11.0 g, 57 mmol) were combined in DMSO (100mL) and treated with anhydrous K₂CO₃ (8.0 g, 58 mmol). The mixture washeated at 90° C. overnight, allowed to cool to room temperature, andthen concentrated under reduced pressure. The residue in dichloromethane(200 mL) was cooled to −78° C. and treated with an excess of TFA (10 mL,130 mmol) dropwise. The mixture was allowed to warm to room temperatureand the layers were separated. The organic layer was washed with brine,dried over Na₂SO₄, filtered, and the filtrate concentrated under reducedpressure to provide the title compound which was used in the next stepwithout further purification.

Example 1EN-(4-tert-butylphenyl)-3′-chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

3′-Chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylic acid (120 mg, 0.35mmol), 4-tert-butylaniline (90.0 mg, 0.6 mmol), and EDCI (145 mg, 0.75mmol) were combined in dichloromethane (3 mL) under N₂ and stirred atroom temperature overnight. The mixture was treated with water and thelayers were separated. The organic layer was concentrated and theresidue was purified via column chromatography (SiO₂, ethylacetate:hexanes, 1:4) to provide the title compound. ¹H NMR (500 MHz,CDCl₃) δ 8.18 (dd, 1H), 7.61 (dd, 1H), 7.46 (d, 2H), 7.38 (s (br), 1H),7.35 (d, 2H), 6.85 (dd, 1H), 6.75 (m, 1H), 4.10 (dd, 2H), 3.58 (dd, 2H),2.68 (m, 2H), 1.30 (s, 9H); MS (ESI) 370 (M+H)⁺.

Example 23′-chloro-N-(4-methylphenyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-methylaniline instead of 4-tert-butylaniline. ¹H NMR (500MHz, CDCl₃) δ 8.18 (dd, 1H), 7.62 (dd, 1H), 7.43 (d, 2H), 7.10 (1H, NH),7.15 (d, 2H), 6.84 (dd, 1H), 6.76 (m, 1H), 4.08 (dd, 2H), 3.58 (dd, 2H),2.66 (m, 2H), 2.32 (s, 3H); MS (ESI) 328 (M+H)⁺.

Example 33′-chloro-N-(4-methoxyphenyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-methoxyaniline instead of 4-tert-butylaniline. ¹H NMR (500MHz, CDCl₃) δ 8.21 (dd, 1H), 7.64 (dd, 1H), 7.55 (s (br) 1H), 7.45 (m,2H), 6.90 (m, 3H), 6.76 (m, 1H), 4.15 (dd, 2H), 3.80 (s, 3H), 3.65 (dd,2H), 2.68 (m, 2H); MS (ESI) 343 (M+H)⁺.

Example 43′-chloro-N-(4-fluorophenyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-fluoroaniline instead of 4-tert-butylaniline. ¹H NMR (500MHz, CDCl₃) δ 8.20 (dd, 1H), 7.66 (dd, 1H), 7.58 (s (br) 1H), 7.54 (m,2H), 7.02 (m, 2H), 6.90 (dd, 1H), 6.76 (m, 1H), 4.15 (dd, 2H), 3.62 (dd,2H), 2.68 (m, 2H); MS (ESI) 331 (M+H)⁺.

Example 53′-chloro-N-(4-chlorophenyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

4-Chloroaniline (13.2 g, 103 mmol),3′-chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylic acid (16.49 g,69.1 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (26.5 g, 138 mmol) were combined in dichloromethane (150mL) and stirred overnight at ambient temperature. The mixture wasdiluted with dichloromethane (200 mL), washed with water (400 mL), 400mL brine, dried with sodium sulfate, filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified bychromatography on silica gel using hexane:ethyl:acetate (7:3) to providethe title compound. ¹H NMR (500 MHz, CDCl₃) δ 8.20 (dd, 1H), 7.70 (dd,1H), 7.62 (s (br) 1H), 7.54 (d, 2H), 7.30 (d, 2H), 6.92 (dd, 1H), 6.76(m, 1H), 4.16 (dd, 2H), 3.64 (dd, 2H), 2.66 (m, 2H); MS (ESI) 349(M+H)⁺.

Example 6N-(4-bromophenyl)-3′-chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-bromoaniline instead of 4-tert-butylaniline. ¹H NMR (500 MHz,CDCl₃) δ 8.20 (dd, 1H), 7.65 (dd, 1H), 7.55 (s (br) 1H), 7.48 (d, 2H),7.44 (d, 2H), 6.88 (dd, 1H), 6.78 (m, 1H), 4.15 (dd, 2H), 3.61 (dd, 2H),2.66 (m, 2H); MS (ESI) 393 (M+H)⁺.

Example 73′-chloro-N-[4-(trifluoromethoxy)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-(trifluoromethoxy)aniline instead of 4-tert-butylaniline. ¹HNMR (500 MHz, CDCl₃) δ 8.20 (dd, 1H), 7.65 (dd, 1H), 7.55 (s (br) 1H),7.48 (d, 2H), 7.44 (d, 2H), 6.88 (dd, 1H), 6.78 (m, 1H), 4.15 (dd, 2H),3.61 (dd, 2H), 2.66 (m, 2H); MS (ESI) 393 (M+H)⁺.

Example 83′-chloro-N-(4-phenoxyphenyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-phenoxyaniline instead of 4-tert-butylaniline. ¹H NMR (500MHz, CDCl₃) δ 8.19 (dd, 1H), 7.62 (dd, 1H), 7.54 (d, 2H), 7.54 (s (br)1H), 7.32 (dd. 2H), 7.08 (t, 1H), 7.00 (m, 4H), 6.85 (dd, 1H), 6.78 (m,1H), 4.12 (dd, 2H), 3.59 (dd, 2H), 2.68 (m, 2H); MS (ESI) 406 (M+H)⁺.

Example 93′-chloro-N-(4-ethylphenyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-ethylaniline instead of 4-tert-butylaniline. ¹H NMR (500 MHz,CDCl₃) δ 8.19 (dd, 1H), 7.62 (dd, 1H), 7.45 (d, 2H), 7.43 (s (br) 1H),7.18 (dd. 2H), 6.84 (dd, 1H), 6.75 (m, 1H), 4.12 (dd, 2H), 3.78 (dd,2H), 2.69 (m, 2H), 2.62 (q, 2H), 1.22 (t, 3H); MS (ESI) 342 (M+H)⁺.

Example 103′-chloro-N-(4-isopropylphenyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-isopropylaniline instead of 4-tert-butylaniline. ¹H NMR (500MHz, CDCl₃) δ 8.19 (dd, 1H), 7.61 (dd, 1H), 7.50 (s (br), 1H), 7.46 (d,2H), 7.18 (dd. 2H), 6.84 (dd, 1H), 6.76 (m, 1H), 4.08 (dd, 2H), 3.56(dd, 2H), 2.85 (m, 1H), 2.68 (m, 2H), 1.22 (d, 6H); MS (ESI) 356 (M+H)⁺.

Example 11N-(3-tert-butylphenyl)-3′-chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 3-tert-butylaniline instead of 4-tert-butylaniline. ¹H NMR (500MHz, CDCl₃) δ 8.19 (dd, 1H), 7.64 (dd, 1H), 7.54 (m, 1H), 7.49 (s (br),1H), 7.43 (m, 1H), 7.28 (d, 1H), 7.16 (m, 1H), 6.86 (dd, 1H), 6.77 (m,1H), 4.12 (dd, 2H), 3.60 (dd, 2H), 2.70 (m, 2H), 1.32 (s, 9H); MS (ESI)369 (M+H)⁺.

Example 12N-1,1′-biphenyl-4-yl-3′-chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 1,1′-biphenyl-4-ylamine instead of 4-tert-butylaniline. ¹H NMR(500 MHz, CDCl₃) δ 8.19 (dd, 1H), 7.62 (m, 3H), 7.58 (m, 5H), 7.42 (dd,2H), 7.32 (t, 1H), 6.86 (dd, 1H), 6.77 (m, 1H), 4.12 (dd, 2H), 3.60 (dd,2H), 2.70 (m, 2H); MS (ESI) 390 (M+H)⁺.

Example 133′-chloro-N-(4-propoxyphenyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-propoxyaniline instead of 4-tert-butylaniline. ¹H NMR (500MHz, CDCl₃) δ 8.19 (dd, 1H), 7.60 (dd, 1H), 7.42 (m, 2H), 7.40 (s (br),1H), 6.85 (m, 3H), 6.75 (m, 1H), 4.08 (dd, 2H), 3.90 (m, 2H), 3.58 (dd,2H), 2.65 (m, 2H), 1.80 (m, 2H), 1.02 (m, 3H); MS (ESI) 372 (M+H)⁺.

Example 143′-chloro-N-[4-(methylthio)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-(methylthio)aniline instead of 4-tert-butylaniline. ¹H NMR(500 MHz, CDCl₃) δ 8.20 (dd, 1H), 7.64 (dd, 1H), 7.52 (m, 3H), 7.25 (d,2H), 6.86 (dd, 1H), 6.76 (m, 1H), 4.12 (dd, 2H), 3.60 (dd, 2H), 2.68 (m,2H), 2.46 (s, 3H); MS (ESI) 360 (M+H)⁺.

Example 153′-chloro-N-(3-fluoro-4-methylphenyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 3-fluoro-4-methylaniline instead of 4-tert-butylaniline. ¹H NMR(500 MHz, CDCl₃) δ 8.19 (dd, 1H), 7.62 (dd, 1H), 7.48 (m, 2H), 7.10 (m,2H), 6.85 (dd, 1H), 6.77 (m, 1H), 4.12 (dd, 2H), 3.58 (dd, 2H), 2.65 (m,2H), 2.22 (s, 3H); MS (ESI) 346 (M+H)⁺.

Example 163′-chloro-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-(trifluoromethyl)aniline instead of 4-tert-butylaniline. ¹HNMR (500 MHz, CDCl₃) δ 8.19 (dd, 1H), 7.72 (d, 2H), 7.64 (dd, 1H), 7.60(d, 2H), 7.58 (s (br), 1H), 6.86 (dd, 1H), 6.82 (m, 1H), 4.14 (dd, 2H),3.59 (dd, 2H), 2.68 (m, 2H); MS (ESI) 382 (M+H)⁺.

Example 173′-chloro-N-(3-fluorophenyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 3-fluoroaniline instead of 4-tert-butylaniline. ¹H NMR (500MHz, CDCl₃) δ 8.19 (dd, 1H), 7.65 (d, 2H), 7.59 (s (br), 1H), 7.54 (m,1H), 7.24 (m, 1H), 7.19 (m, 1H), 6.86 (dd, 1H), 6.82 (m, 1H), 6.78 (m,1H), 4.14 (dd, 2H), 3.60 (dd, 2H), 2.66 (m, 2H); MS (ESI) 332 (M+H)⁺.

Example 183′-chloro-N-[4-(dimethylamino)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using N,N-dimethyl-1,4-benzenediamine instead of 4-tert-butylaniline.¹H NMR (500 MHz, CDCl₃) δ 8.24 (br s, 1H), 8.20 (dd, 1H), 7.76 (m, 3H),7.48 (d, 2H), 6.85 (dd, 1H), 6.82 (m, 1H), 4.19 (dd, 2H), 3.68 (dd, 2H),3.17 (s, 6H), 2.68 (m, 2H); MS (ESI) 357 (M+H)⁺.

Example 193′-chloro-N-[4-(diethylamino)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using N,N-diethyl-1,4-benzenediamine instead of 4-tert-butylaniline.¹H NMR (500 MHz, CDCl₃) δ 8.21 (dd, 1H), 8.04 (s (br), 1H), 7.81 (d,2H), 7.74 (dd, 1H), 7.51 (d, 2H), 6.92 (dd, 1H), 6.82 (m, 1H), 4.20 (dd,2H), 3.68 (dd, 2H), 3.52 (m, 4H), 2.69 (m, 2H), 1.15 (t, 6H); MS (ESI)385 (M+H)⁺.

Example 203′-chloro-N-[4-(1-piperidinyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-(1-piperidinyl)aniline instead of 4-tert-butylaniline. ¹H NMR(500 MHz, CDCl₃) δ 8.41 (br s, 1H), 8.20 (dd, 1H), 7.75 (d, 2H), 7.72(dd, 1H), 7.50 (d, 2H), 6.92 (dd, 1H), 6.82 (m, 1H), 4.16 (dd, 2H), 3.64(dd, 2H), 3.44 (m, 4H), 2.69 (m, 2H), 2.08 (m, 4H), 1.72 (m, 2H); MS(ESI) 397 (M+H)⁺.

Example 213′-chloro-N-[4-(4-morpholinyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-(4-morpholinyl)aniline instead of 4-tert-butylaniline. ¹H NMR(500 MHz, CDCl₃) δ 8.42 (s (br), 1H), 8.20 (dd, 1H), 7.92 (dd, 1H), 7.76(d, 2H), 7.44 (d, 2H), 7.04 (dd, 1H), 6.76 (m, 1H), 4.28 (m, 2H), 4.10(m, 4H), 3.81 (dd, 2H), 3.52 (m, 4H), 2.71 (m, 2H); MS (ESI) 399 (M+H)⁺.

Example 22N-[4-(1-azepanyl)phenyl]-3′-chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example1E using 4-(1-azepanyl)aniline instead of 4-tert-butylaniline. ¹H NMR(500 MHz, CDCl₃) δ 8.58 (s (br), 1H), 8.20 (dd, 1H), 7.86 (dd, 1H), 7.74(d, 2H), 7.45 (d, 2H), 7.01 (dd, 1H), 6.78 (m, 1H), 4.24 (m, 2H), 3.75(dd, 2H), 3.62 (m, 4H), 2.70 (m, 2H), 2.08 (m, 4H), 1.82 (m, 4H); MS(ESI) 411 (M+H)⁺.

Example 23N-(4-tert-butylphenyl)-3-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamideExample 23A methyl 1-benzyl-5-oxo-2-pyrrolidinecarboxylate

1-Benzyl-5-oxo-2-pyrrolidinecarboxylic acid (9.69 g, 44.2 mmol) inmethanol (75 mL) was treated with sulfuric acid (0.5 mL) and refluxedfor 2.5 hours. The mixture was allowed to cool to room temperature andconcentrated under reduced pressure. The residue was dissolved in ethylacetate and washed with saturated sodium bicarbonate solution. The ethylacetate phase was concentrated under reduced pressure to provide thetitle compound which was used in the next step without furtherpurification.

MS (ESI) m/z: 234 (M+H)⁺; ¹H NMR (CDCl₃) δ 2.08 (m, 1H), 2.25 (m, 1H),2.43 (m, 1H), 2.55 (m, 1H), 3.68 (s, 3H), 3.99 (dd, 1H), 4.01 (d, 1H),5.02 (d, 1H), 7.22 (m, 2H), 7.30 (m, 3H).

Example 23B methyl 1-benzyl-5-thioxo-2-pyrrolidinecarboxylate

Methyl 1-benzyl-5-oxo-2-pyrrolidinecarboxylate (18.15 g, 77.8 mmol) andLawesson's reagent (31.5 g, 77.9 mmol) were combined in drytetrahydrofuran (100 mL) and stirred overnight at room temperature. Themixture was filtered, the filter cake was rinsed with tetrahydrofuran,and the filtrate was concentrated under reduced pressure. The residuewas dissolved in ethyl acetate and washed with saturated sodiumbicarbonate solution. The organic phase was concentrated under reducedpressure and the residue was purified by chromatography on silica gel(3:1, hexanes:ethyl acetate) to provide the title compound. MS (ESI)m/z: 250 (M+H)⁺; ¹H NMR (CDCl₃) δ 2.17 (m, 1H), 2.27 (m, 1H), 3.15 (m,2H), 3.69 (s, 3H), 4.30 (dd, 1H), 4.37 (d, 1H), 5.73 (d, 1H), 7.32 (m,5H).

Example 23C1-benzyl-2-(methoxycarbonyl)-5-(methylthio)-3,4-dihydro-2H-pyrroliumiodide

Methyl 1-benzyl-5-thioxo-2-pyrrolidinecarboxylate (16.5 g, 66.2 mmol) iniodomethane (70 mL) was stirred overnight at room temperature. Themixture was concentrated under reduced pressure to provide the titlecompound which was used in the next step without further purification.¹H NMR (CDCl₃) δ 2.24 (m, 1H), 3.04 (s, 3H), 3.16 (m, 1H), 3.25 (m, 1H),3.63 (s, 3H), 4.29 (dd, 1H), 4.72 (d, 1H), 4.89 (dd, 1H), 5.14 (d, 1H),7.43 (m, 3H), 7.51 (m, 2H).

Example 23D methyl 1-benzyl-5-(nitromethylene)-2-pyrrolidinecarboxylate

1-Benzyl-2-(methoxycarbonyl)-5-(methylthio)-3,4-dihydro-2H-pyrroliumiodide (25.68 g, 65.6 mmol) in dry N,N-dimethylformamide (80 mL) wastreated with nitromethane (17.8 mL, 328 mmol) and diisopropylethyl amine(12.6 mL, 72.2 mmol) and stirred overnight at room temperature. Themixture was heated at 60° C. for 5 hours, allowed to cool to roomtemperature, and concentrated under reduce pressure. The residue waspurified by chromatography on silica gel (3:2 hexanes:ethyl acetate) toprovide the title compound. MS (ESI) m/z: 277 (M+H)⁺; ¹H NMR (CDCl₃) δ2.22 (m, 1H), 2.34 (m, 1H), 3.39 (5, 1H), 3.69 & 3.75 (dd & dd, 1H),3.72 (s, 3H), 4.24 (dd, 1H), 4.30 (d, 1H), 4.51 (d, 1H), 6.87 (s, 1H),7.16 (dd, 2H), 7.35 (m, 3H).

Example 23E 8-benzyl-3,8-diazabicyclo[3.2.1]octan-2-one

Methyl 1-benzyl-5-(nitromethylene)-2-pyrrolidinecarboxylate (9.92 g,35.9 mmol) and 5% platinum on activated carbon (11.25 g) were combinedin methanol (100 mL) and shaken for 56 hours at ambient temperatureunder a hydrogen atmosphere (60 psi). The mixture was filtered and thefiltrate concentrated to provide the title compound. MS (DCI/NH₃) m/z:217 (M+H)⁺.

Example 23F 8-benzyl-3,8-diazabicyclo[3.2.1]octane

8-Benzyl-3,8-diazabicyclo[3.2.1]octan-2-one (5.87 g, 27.1 mmol) in drytetrahydrofuran (40 mL) was treated with 1M lithium aluminum hydride inTHF (81.4 mL), heated at 60° C. for 2 hours, and then allowed to cool toroom temperature and stir overnight. The mixture was cooled to 0° C. andtreated in succession with water (4.4 mL), tetrahydrofuran (200 mL), 15%sodium hydroxide solution (4.4 mL), and water (13.3 mL). The mixture wasfiltered and the filter cake was rinsed with ethyl acetate. The filtratewas concentrated under reduced pressure to provide the title compound.MS (DCI/NH₃) m/z: 203 (M+H)⁺.

Example 23G 8-benzyl-3-(trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octane

8-Benzyl-3,8-diazabicyclo[3.2.1]octane (5.18 g, 25.6 mmol) andtriethylamine (17.8 mL, 128 mmol) were combined in dry dichloromethane(50 mL) at 0° C., treated with trifluoroacetic anhydride in 1 mLportions (8.9 mL, 64 mmol), and stirred overnight at room temperature.The mixture was concentrated under reduced pressure and the residue waspurified by chromatography on silica gel (9:1 hexanes:ethyl acetate) toprovide the title compound. MS (DCI/NH₃) m/z: 299 (M+H)⁺; ¹H NMR (CDCl₃)δ 1.66 (m, 2H), 2.06 (br, 2H), 3.08 (d, 1H), 3.25 (d, 2H), 3.53 (m, 4H),4.12 (d, 1H), 7.34 (m, 5H).

Example 23H tert-butyl3-(trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

8-Benzyl-3-(trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octane (1.95 g, 6.54mmol) and di-tert-butyl dicarbonate (2.14 g, 9.81 mmol) were combined inethyl acetate (75 mL) and treated with Pearlman's catalyst (216 mg)under a hydrogen atmosphere (1 atmosphere) with stirring for 48 hours atroom temperature. The mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue in ethyl acetate (150mL) was treated with L-aspartic acid and stirred for 2 hours. Themixture was washed with saturated sodium bicarbonate solution andconcentrated under reduced pressure to provide the title compound. ¹HNMR (CDCl₃) δ 1.48 (s, 9H), 1.70 (m, 2H), 1.98 (m, 2H), 3.06 (d, 1H),3.45 (d, 1H), 3.70 (d, 1H), 4.23 (d, 1H), 4.30 (br, 2H).

Example 23I tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate

tert-Butyl3-(trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.54mmol) in methanol (85 mL) was treated with ammonium hydroxide (8.5 mL)and stirred overnight at room temperature. The mixture was concentratedunder reduced pressure and purified by chromatography on silica gel (5%MeOH, 0.5% NH₄OH in CH₂Cl₂; then 10% MeOH, 1% NH₄OH in CH₂Cl₂) toprovide the title compound. MS (DCI/NH₃) m/z: 213 (M+H)⁺; ¹H NMR (CDCl₃)δ 1.47 (s, 9H), 1.81 (m, 2H), 1.94 (m, 2H), 2.65 (dd, 2H), 3.00 (br,2H), 4.11 (br, 2H).

Example 23J tert-butyl3-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

tert-Butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (435 mg, 2.26mmol), 2-bromo-3-chloropyridine (400 mg, 1.88 mmol), and potassiumcarbonate (390 mg, 2.83 mmol) were combined in dry dimethylformamide (10mL) and stirred at 120° C. for 48 hours. The mixture was allowed to coolroom temperature, diluted with ethyl acetate, filtered, and the filtratewas concentrated under reduced pressure. The residue was purified bychromatography on silica gel (85:15 hexanes:ethyl acetate) to providethe title compound. MS (ESI) m/z: 268 (100%), 324.0 (M+H)⁺; ¹H NMR(CDCl₃) δ 1.48 (s, 9H), 1.92 (m, 2H), 2.07 (m, 2H), 3.13 (d, 2H), 3.59(br, 2H), 4.30 (br, 2H), 6.84 (dd, 1H), 7.58 (dd, 1H), 8.17 (dd, 1H).

Example 23K 3-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane

tert-Butyl3-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(419 mg, 1.29 mmol) in dry dichloromethane (5 mL) was treated withtrifluoroacetic acid and stirred at room temperature for an hour. Themixture was concentrated under reduced pressure and the residue wastreated with 1N sodium hydroxide solution. The mixture was extractedwith ethyl acetate and the organic phase was concentrated under reducedpressure to provide the title compound. MS (ESI) m/z: 224 (M+H)⁺; ¹H NMR(CDCl₃) δ 1.86 (m, 2H), 2.09 (m, 2H), 3.09 (d, 2H), 3.63 (m, 4H), 6.81(dd, 1H), 7.56 (dd, 1H), 8.16 (dd, 1H).

Example 23LN-(4-tert-butylphenyl)-3-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

3-(3-Chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane (129 mg, 577μmol) in dry dichloromethane (5 mL) was treated with1-tert-butyl-4-isocyanatobenzene (101 mg, 577 μmol) and allowed to stirovernight at room temperature. The mixture was concentrated underreduced pressure and the residue was purified by chromatography onsilica gel (3:1, hexanes:ethyl acetate) to provide the title compound.MS (DCI/NH₃) m/z: 399 (M+H)⁺; ¹H NMR (CDCl₃) δ 1.30 (s, 9H), 2.01 (m,2H), 2.17 (m, 2H), 3.25 (d, 2H), 3.64 (dd, 2H), 4.38 (dd, 2H), 6.32 (s,1H), 6.86 (dd, 1H), 7.32 (s, 4H), 7.59 (dd, 1H), 8.17 (dd, 1H).

Example 243-(3-chloro-2-pyridinyl)-N-(3,4-dichlorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared using the procedure described in Example23L using 1,2-dichloro-4-isocyanatobenzene instead of1-tert-butyl-4-isocyanatobenzene. MS (ESI) m/z: 413 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.87 (m, 2H), 2.01 (m, 2H), 3.06 (d, 2H), 3.55 (dd, 2H),4.53 (s, 2H), 7.01 (dd, 1H), 7.47 (m, 2H), 7.79 (dd, 1H), 7.90 (dd, 1H),8.21 (dd, 1H), 8.90 (s, 1H).

Example 253-(3-chloro-2-pyridinyl)-N-[3-(trifluoromethyl)phenyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared using the procedure described in Example23L using 1-isocyanato-3-(trifluoromethyl)benzene instead of1-tert-butyl-4-isocyanatobenzene. MS (ESI) m/z: 411 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.88 (m, 2H), 2.02 (m, 2H), 3.07 (d, 2H), 3.53 (dd, 2H),4.55 (dd, 2H), 7.00 (dd, 1H), 7.27 (dd, 1H), 7.48 (t, 1H), 7.80 (dd,1H), 7.99 (t, 1H), 8.21 (dd, 1H), 8.95 (s, 1H).

Example 263-(3-chloro-2-pyridinyl)-N-[4-(trifluoromethyl)phenyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared using the procedure described in Example23L using 1-isocyanato-4-(trifluoromethyl)benzene instead of1-tert-butyl-4-isocyanatobenzene. MS (ESI) m/z: 411 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.88 (m, 2H), 2.02 (m, 2H), 3.07 (d, 2H), 3.55 (dd, 2H),4.56 (dd, 2H), 7.00 (dd, 1H), 7.60 (d, 2H), 7.75 (d, 2H), 7.80 (dd, 1H),8.21 (dd, 1H), 9.00 (s, 1H).

Example 273-(3-chloro-2-pyridinyl)-N-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared using the procedure described in Example23L using 1-fluoro-4-isocyanatobenzene instead of1-tert-butyl-4-isocyanatobenzene. MS (ESI) m/z: 361 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.86 (m, 2H), 2.00 (m, 2H), 3.06 (d, 2H), 3.53 (dd, 2H),4.51 (dd, 2H), 7.01 (dd, 1H), 7.08 (t, 2H), 7.51 (dd, 2H), 7.79 (dd,1H), 8.21 (dd, 1H), 8.65 (s, 1H).

Example 28N-(4-chlorophenyl)-3-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared using the procedure described in Example23L using 1-chloro-4-isocyanatobenzene instead of1-tert-butyl-4-isocyanatobenzene. MS (ESI) m/z: 377 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.86 (m, 2H), 2.00 (m, 2H), 3.06 (d, 2H), 3.54 (dd, 2H),4.52 (s, 2H), 7.01 (dd, 1H), 7.29 (d, 2H), 7.55 (d, 2H), 7.79 (dd, 1H),8.21 (dd, 1H), 8.74 (s, 1H).

Example 29N-(4-bromophenyl)-3-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared using the procedure described in Example23L using 1-bromo-4-isocyanatobenzene instead of1-tert-butyl-4-isocyanatobenzene. MS (ESI) m/z: 423 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.86 (m, 2H), 2.00 (m, 2H), 3.06 (d, 2H), 3.54 (dd, 2H),4.53 (s, 2H), 7.01 (dd, 1H), 7.41 (d, 2H), 7.51 (d, 2H), 7.79 (dd, 1H),8.21 (dd, 1H), 8.75 (s, 1H).

Example 303-(3-chloro-2-pyridinyl)-N-(4-iodophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared using the procedure described in Example23L using 1-iodo-4-isocyanatobenzene instead of1-tert-butyl-4-isocyanatobenzene.

MS (ESI) m/z: 469 (M+H)⁺; ¹H NMR (DMSO-d₆) δ 1.86 (m, 2H), 2.00 (m, 2H),3.05 (d, 2H), 3.53 (dd, 2H), 4.52 (d, 2H), 7.01 (dd, 1H), 7.38 (d, 2H),7.56 (d, 2H), 7.79 (dd, 1H), 8.21 (dd, 1H), 8.72 (s, 1H).

Example 31N-(4-butylphenyl)-3-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared using the procedure described in Example23L using 1-butyl-4-isocyanatobenzene instead of1-tert-butyl-4-isocyanatobenzene. MS (ESI) m/z: 399 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 0.89 (t, 3H), 1.29 (6, 2H), 1.52 (5, 2H), 1.86 (m, 2H), 1.99(m, 2H), 2.50 (t, 2H), 3.06 (d, 2H), 3.52 (dd, 2H), 4.51 (s, 2H), 7.00(dd, 1H), 7.05 (d, 2H), 7.39 (d, 2H), 7.79 (dd, 1H), 8.21 (dd, 1H), 8.52(s, 1H).

Example 323-(3-chloro-2-pyridinyl)-N-(4-isopropylphenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared using the procedure described in Example23L using 1-isocyanato-4-isopropylbenzene instead of1-tert-butyl-4-isocyanatobenzene. MS (ESI) m/z: 385 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.17 (d, 6H), 1.86 (m, 2H), 1.99 (m, 2H), 2.81 (7, 2H), 3.06(d, 2H), 3.52 (dd, 2H), 4.51 (s, 2H), 7.00 (dd, 1H), 7.11 (d, 2H), 7.41(d, 2H), 7.79 (dd, 1H), 8.21 (dd, 1H), 8.54 (s, 1H).

Example 333-(3-chloro-2-pyridinyl)-N-{4-[(trifluoromethyl)thio]phenyl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide

The title compound was prepared using the procedure described in Example23L using 1-isocyanato-4-[(trifluoromethyl)thio]benzene instead of1-tert-butyl-4-isocyanatobenzene. MS (ESI) m/z: 443 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.88 (m, 2H), 2.01 (m, 2H), 3.07 (d, 2H), 3.55 (dd, 2H),4.55 (s, 2H), 7.01 (dd, 1H), 7.58 (d, 2H), 7.70 (d, 2H), 7.80 (dd, 1H),8.21 (dd, 1H), 8.98 (s, 1H).

Example 34N-(4-tert-butylphenyl)-8-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxamideExample 34A 8-benzyl-3,8-diazabicyclo[3.2.1]octane

tert-Butyl3-(trifluoroacetyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.63 g,5.46 mmol) in methanol (50 mL) was treated with ammonium hydroxide (7.5mL) and stirred overnight at room temperature.

Example 34B tert-butyl8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

8-Benzyl-3,8-diazabicyclo[3.2.1]octane (5.46 mmol) and di-tert-butyldicarbonate (1.79 g, 8.20 mmol) were combined in ethyl acetate (25 mL)and stirred overnight at room temperature. The mixture was concentratedunder reduced pressure, dissolved in ethyl acetate (150 mL), treatedwith L-aspartic acid (2.18 g, 16.4 mmol), and stirred overnight. Themixture was washed with saturated sodium bicarbonate solution andconcentrated under reduced pressure to provide the title compound.

Example 34C tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate

tert-Butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.46mmol, 203 mg) and Pearlman's catalyst were combined in methanol under ahydrogen atmosphere (1 atmosphere) stirred overnight at roomtemperature. Purged with nitrogen, filtered off the catalyst, andconcentrated the filtrate to a yellow liquid. The mixture was filteredand the filtrate was concentrated under reduced pressure. The residuewas purified by chromatography on silica gel (5% MeOH, 0.5% NH₄OH inCH₂Cl₂, then 10% MeOH, 1% NH₄OH in CH₂Cl₂) to provide the titlecompound. MS (DCI/NH₃) m/z: 213 (M+H)⁺; ¹H NMR (CDCl₃) δ 1.45 (s, 9H),1.75 (br, 4H), 2.93 (d, 1H), 3.01 (d, 1H), 3.47 (d, 2H), 3.68 (d, 1H),3.81 (d, 1H).

Example 34D tert-butyl8-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

tert-Butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (454 mg, 2.36mmol) and 2-bromo-3-chloropyridine (418 mg, 1.97 mmol) were combined indry N,N-dimethylformamide (10 mL) and treated with potassium carbonate(408 mg, 2.95 mmol). After stirring at 120° C. for 48 hours, the mixturewas allowed to cool to room temperature, diluted with ethyl acetate,filtered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography on silica gel (4:1, hexanes:ethylacetate) to provide the title compound. MS (ESI) m/z: 324 (M+H)⁺; ¹H NMR(CDCl₃) δ 1.47 (s, 9H), 1.77 (m, 2H), 1.93 (m, 2H), 3.22 (d, 1H), 3.31(d, 1H), 3.76 (d, 1H), 3.90 (d, 1H), 4.53 (d, 2H), 6.76 (dd, 1H), 7.56(dd, 1H), 8.09 (dd, 1H).

Example 34E 8-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane

tert-Butyl8-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate(285 mg, 880 μmol) in dry dichloromethane (2 mL) was treated withtrifluoroacetic acid (2 mL). After stirring at ambient temperature for30 minutes, the mixture was concentrated under reduced pressure and theresidue was treated with 1N sodium hydroxide solution. The mixture wasextracted with ethyl acetate and the organic phase was concentratedunder reduced pressure to provide the title compound. MS (DCI/NH₃) m/z:224 (M+H)⁺; ¹H NMR (CDCl₃) δ 1.87 (m, 2H), 1.97 (m, 2H), 2.75 (dd, 2H),3.24 (dd, 2H), 4.44 (dd, 2H), 6.73 (dd, 1H), 7.54 (dd, 1H), 8.08 (dd,1H).

Example 34FN-(4-tert-butylphenyl)-8-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxamide

8-(3-Chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane (102 mg, 456μmol) and 1-tert-butyl-4-isocyanatobenzene (80 mg, 456 μmol) werecombined in dry dichloromethane (4.5 mL) and stirred overnight at roomtemperature. The mixture was concentrated and the residue was purifiedby chromatography on silica gel (7:3, hexanes:ethyl acetate) to providethe title compound.

MS (ESI) m/z: 399 (M+H)⁺;

¹H NMR (DMSO-d₆) δ 1.25 (s, 9H), 1.73 (m, 2H), 1.85 (m, 2H), 3.20 (dd,2H), 3.92 (dd, 2H), 4.51 (dd, 2H), 6.94 (dd, 1H), 7.24 (d, 2H), 7.37 (d,2H), 7.79 (dd, 1H), 8.17 (dd, 1H), 8.30 (s, 1H).

Example 358-(3-chloro-2-pyridinyl)-N-[4-(trifluoromethyl)phenyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxamide

The title compound was prepared using the procedure described in Example34F using 1-isocyanato-4-(trifluoromethyl)benzene instead of1-tert-butyl-4-isocyanatobenzene. MS (ESI) m/z: 411 (M+H)⁺; ¹H NMR(DMSO-d₆) δ 1.74 (m, 2H), 1.87 (m, 2H), 3.25 (d, 2H), 3.95 (dd, 2H),4.53 (dd, 2H), 6.95 (dd, 1H), 7.58 (d, 2H), 7.70 (d, 2H), 7.80 (dd, 1H),8.17 (dd, 1H), 8.78 (s, 1H).

Example 37N-(4-tert-butylphenyl)-1-(3-chloro-2-pyridinyl)-(cis)-3-hydroxy-4′-piperidinecarboxamideExample 37A ethyl 1-benzyl-3-hydroxy-4-piperidinecarboxylate

Ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate (1.0 g, 3.8 mmol) indiethyl ether (50 mL) was treated with lithium aluminumhydride (150 mg,3.9 mmol) at and −78° C. After stirring at −78° C. for 30 minutes, themixture was allowed to warm to room temperature over 2 hours. Themixture was quenched with saturated ammonium chloride. Standard work-upgave a crude product which was purified via chromatography (SiO₂, ethylacetate:hexanes, 1:6) to provide the title compound. MS (EI, M+H)⁺ 264.

Example 37B ethyl 3-hydroxy-4-piperidinecarboxylate

Ethyl 1-benzyl-3-hydroxy-4-piperidinecarboxylate in ethanol (10 mL) wastreated with Pd(OH)₂ (20% on carbon, 50 mg) under a hydrogen atmosphere(1 atm) and stirred for 5 hours. The reaction mixture was filtered andthe filtrate was concentrated under reduced pressure.

Example 37C ethyl1-(3-chloro-2-pyridinyl)-3-hydroxy-4-piperidinecarboxylate

Ethyl 3-hydroxy-4-piperidinecarboxylate, 2-bromo-3-chloropyridine (700mg, 3.6 mmol), and potassium carbonate (1.0 g, 7.2 mmol) were and heatedat 90° C. for 2 days. Standard work-up gave the title compound.

Example 37D 1-(3-chloro-2-pyridinyl)-3-hydroxy-4-piperidinecarboxylicacid

Ethyl 1-(3-chloro-2-pyridinyl)-3-hydroxy-4-piperidinecarboxylate inwater (55 mL) was treated with sodium methoxide (0.5 M, 8 mL, 4.0 mmol)at room temperature. After 2 hours, the mixture was concentrated underreduced pressure and the residue was purified by column chromatographyto provide the title compound. MS (EI, M+H)⁺ 257.

Example 37EN-(4-tert-butylphenyl)-1-(3-chloro-2-pyridinyl)-(cis)-3-hydroxy-4-piperidinecarboxamide

1-(3-Chloro-2-pyridinyl)-3-hydroxy-4-piperidinecarboxylic acid,tert-butylanaline (255 mg, 1.7 mmol), and EDCI (380 mg, 2.0 mmol) werecombined at room temperature. The mixture was allowed to stir for 8hours and standard work-up provided crude product which was purified bycolumn chromatography to provide the cis and trans analogues. ¹H NMR(500 MHz, CDCl₃) δ 8.15 (dd, 1H), 7.68 (dd, 1H), 7.46 (m, 2H), 7.32 (m,2H), 6.95 (dd, 1H), 4.32 (m, 1H), 4.08 (m, 1H), 3.95 (m, 1H), 3.25 (m,2H), 2.56 (m, 1H), 1.92 (m, 2H), 1.28 (s, 9H); MS (ESI, M+H)⁺ 388.

Example 38N-(4-tert-butylphenyl)-1-(3-chloro-2-pyridinyl)-(trans)-3-hydroxy-4-piperidinecarboxamide

The title compound was isolated from the purification step in Example37E. ¹H NMR (500 MHz, CDCl₃) δ 8.26 (dd, 1H), 7.96 (s (br), 1H), 7.64(dd, 1H), 7.45 (m, 2H), 7.34 (m, 2H), 6.86 (dd, 1H), 4.22 (ddd, 1H),4.05 (m, 1H), 3.96 (m, 1H), 3.02 (m, 1H), 2.94 (m, 1H), 2.42 (m, 1H),2.14 (m, 1H), 1.96 (m, 1H), 1.30 (s, 9H); MS (ESI, M+H)⁺ 388.

Example 391-(3-chloro-2-pyridinyl)-4-hydroxy-N-[4-(trifluoromethyl)phenyl]-4-piperidinecarboxamideExample 39A methyl 1-benzyl-4-hydroxy-4-piperidinecarboxylate

1-Benzyl-4-hydroxy-4-piperidinecarbonitrile (30.0 g, 118 mmol) inmethanol (590 mL) and concentrated HCl (590 mL) was heated at reflux for18 hours. The product was obtained following chromatography (SiO₂, ethylacetate:hexane, 1:4). MS (EI, M+H)⁺ 250.

Example 39B methyl 4-hydroxy-4-piperidinecarboxylate

Methyl 1-benzyl-4-hydroxy-4-piperidinecarboxylate in methanol wastreated with Pd(OH)₂ (20% on carbon, 500 mg) under a hydrogenatmosphere. The mixture was allowed to stir at room temperature for 12hours, filtered, and the filtrate was concentrated under reducedpressure.

Example 39C methyl1-(3-chloro-2-pyridinyl)-4-hydroxy-4-piperidinecarboxylate

Methyl 1-benzyl-4-hydroxy-4-piperidinecarboxylate (15.0 g, 77 mmol),2,3-dichloropyridine (12.0 g, 81 mmol), and potassium carbonate (15.0 g,108.7 mmol) were combined in DMF (200 mL) and heated at 90° C. for 2days. The mixture was allowed to cool to room temperature, concentrated,and standard work-up provided a residue that was purified viachromatography (SiO₂, ethyl acetate:hexanes, 1:6) to provide the titlecompound MS (EI, M+H)⁺ 271.

Example 39D 1-(3-chloro-2-pyridinyl)-4-hydroxy-4-piperidinecarboxylicacid

The title compound was prepared using the procedure described in Example37D substituting methyl1-(3-chloro-2-pyridinyl)-4-hydroxy-4-piperidinecarboxylate for ethyl1-(3-chloro-2-pyridinyl)-3-hydroxy-4-piperidinecarboxylate.

Example 39E1-(3-chloro-2-pyridinyl)-4-hydroxy-N-[4-(trifluoromethyl)phenyl]-4-piperidinecarboxamide

1-(3-Chloro-2-pyridinyl)-4-hydroxy-4-piperidinecarboxylic acid, EDCI(525 mg, 2.7 mmol), and 4-(trifluoromethyl)aniline in dichloromethane(10 mL) were combined at room temperature and stirred overnight.Standard work-up gave a crude product which was purified viachromatography (SiO₂, ethyl acetate:hexanes, 1:9). ¹H NMR (500 MHz,CDCl₃) δ 8.90 (s (br), 1H), 8.20 (dd, 1H), 7.74 (d, 2H), 7.61 (m, 3H),6.86 (dd, 1H), 3.80 (m, 2H), 3.18 (m, 2H), 2.50 (m, 2H), 1.78 (m, 2H);MS (ESI, M+H)⁺ 400.

Example 40N-(4-tert-butylphenyl)-3′-(trifluoromethyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamideExample 40A 1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-one

2-Chloro-3-(trifluoromethyl)pyridine (11.92 g, 65.7 mmol)), K₂CO₃ (19.10g, 138 mmol), and 1,4-dioxa-8-azaspiro[4.5]decane (8.85 mL, 69.0 mmol)were combined in DMSO (65 mL) and stirred at 100° C. for 3 hours. Themixture was treated with additional 1,4-dioxa-8-azaspiro[4.5]decane (2.0mL, 16 mmol), stirred for 2 hours, treated with additional1,4-dioxa-8-azaspiro[4.5]decane (1.0 mL, 7.8 mmol), and stirred for 1hour. The mixture was diluted with diethyl ether (200 mL), washed withwater (250 mL), washed with brine (100 mL), dried (Na₂SO₄), filtered,and the filtrate was concentrated under reduced pressure. The residuewas dissolved in concentrated HCl (25 mL), stirred for 3 hours, basifiedwith concentrated NH₄OH, extracted with CH₂Cl₂, and the phasesseparated. The organic phase was dried (Na₂SO₄), filtered, and thefiltrate concentrated under reduced pressure. The residue was purifiedvia flash chromatography (20% to 40% diethyl ether/hexanes) to providethe title compound.

Example 40B methyl3′-(trifluoromethyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylate

Lithium diisopropyl amide (37.3 mmol) in THF (75 mL) at −78° C. wastreated with 1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-one (8.30 g,34.0 mmol) in THF (25 mL) and stirred for 45 minutes. The mixture wastreated with solid PhNTf₂ (14.0 g, 39.1 mmol), stirred for 1 hour, andconcentrated under reduced pressure. The residue was diluted with ethylacetate:hexanes (1:1), washed with 1N NaOH, dried (Na₂SO₄), filteredthrough a silica plug, and the filtrate was concentrated under reducedpressure. The residue, triethylamine (14.2 mL, 102 mmol), andPdCl₂(PPh₃)₂ (0.944 g, 1.34 mmol) were combined in methanol (7.00 mL,173 mmol) and DMF (100 mL) and saturated with carbon monoxide gas(bubbling 15 minutes). The mixture was heated at 80° C. under a carbonmonoxide atmosphere (1 atm) overnight. The mixture was concentrated tohalf volume, diluted with diethyl ether, washed with water, brine, dried(Na₂SO₄), filtered, and the filtrate was concentrated under reducedpressure. The residue was purified by flash chromatography (6% ethylacetate/hexanes) to provide the title compound.

Example 40C3′-(trifluoromethyl)-3,6-dihydro-2H-12′-bipyridine-4-carboxylic acid

Methyl 3′-(trifluoromethyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylate(15 mL) in THF (30 mL) was treated with 1N NaOH (27 mL) and stirred for2 hours. The mixture was treated with additional 1N NaOH (16 mL),stirred for 1 hour, treated with 1N NaOH (14.5 mL), and stirred for 1hour. The mixture was diluted with water and extracted with CH₂Cl₂. Theaqueous layer was then acidified with concentrated HCl and extractedwith CHCl₃. The organic layer was dried (Na₂SO₄), filtered, and thefiltrate was concentrated under reduced pressure to provide the titlecompound.

Example 40DN-(4-tert-butylphenyl)-3′-(trifluoromethyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

3′-(Trifluoromethyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylic acid(0.300 g, 1.10 mmol) and a catalytic amount of DMF were combined inCH₂Cl₂ (4.0 mL) and treated with (COCl)₂ (0.14 mL, 1.6 mmol). Themixture was stirred for 90 minutes, diluted with toluene (0.5 mL) andconcentrated to dryness. The residue was dissolved in CH₂Cl₂ (4.0 mL)treated with pyridine (0.14 mL, 1.7 mmol), a catalytic amount of DMAP,and 4-tert-butylaniline (0.21 mL, 1.3 mmol). After 1 hour, the mixturewas diluted with water and extracted with CH₂Cl₂. The organic phase wasdried (Na₂SO₄), filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography (2.5%ethyl acetate/CH₂Cl₂) to provide the title compound. ¹H NMR (300 MHz,CDCl₃) δ 8.42 (dd, 1H), 7.89 (dd, 1H), 7.47 (d, 3H), 6.98 (dd, 1H), 6.76(s, 1H), 4.06 (q, 2H), 3.53 (t, 2H), 2.67 (m, 2H); MS (m/z) 404.

Example 41N-(4-chlorophenyl)-3′-(trifluoromethyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example40D using 4-chloroaniline instead of 4-tert-butylaniline. ¹H NMR (300MHz, CDCl₃) δ 8.42 (dd, 1H), 7.89 (dd, 1H), 7.51 (dd, 2H), 7.43 (brs,1H), 7.30 (d, 2H), 6.99 (dd, 1H), 6.77 (sept, 1H), 4.05 (q, 2H), 3.51(t, 2H), 2.65 (m, 2H); MS (m/z) 382.

Example 42N-[4-(trifluoromethoxy)phenyl]-3′-(trifluoromethyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example40D using 4-(trifluoromethoxy)aniline instead of 4-tert-butylaniline. ¹HNMR (300 MHz, CDCl₃) δ 8.44 (dd, 1H), 7.90 (dd, 1H), 7.59 (d, 2H), 7.48(brs, 1H), 7.20 (d, 2H), 7.00 (dd, 1H), 6.79 (m, 1H), 4.07 (q, 2H), 3.53(t, 2H), 2.67 (m, 2H); MS (m/z) 432.

Example 433′-(trifluoromethyl)-N-{4-[(trifluoromethyl)thio]phenyl}-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example40D using 4-[(trifluoromethyl)thio]aniline instead of4-tert-butylaniline. ¹H NMR (300 MHz, CDCl₃) δ 8.43 (dd, 1H), 7.90 (dd,1H), 7.66 (d, 2H), 7.62 (d, 2H), 7.53 (brs, 1H), 7.00 (dd, 1H), 6.79 (m,1H), 4.07 (q, 2H), 3.52 (t, 2H), 2.67 (m, 2H); MS (m/z) 448.

Example 443′-(trifluoromethyl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example40D using 4-[(trifluoromethyl)sulfonyl]aniline instead of4-tert-butylaniline. ¹H NMR (300 MHz, CDCl₃) δ 8.43 (dd, 1H), 8.00 (dd,1H), 7.88-7.92 (m, 3H), 7.75 (brs, 1H), 7.02 (dd, 1H), 6.85 (m, 1H),4.09 (q, 2H), 3.52 (t, 2H), 2.68 (m, 2H); MS (m/z) 480.

Example 45N-(3-fluoro-4-methylphenyl)-3′-(trifluoromethyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using the procedure described in Example40D using 3-fluoro-4-methylaniline instead of 4-tert-butylaniline. ¹HNMR (300 MHz, CDCl₃) δ 8.42 (dd, 1H), 7.88 (dd, 1H), 7.47 (dd, 1H), 7.40(brs, 1H), 7.05-7.15 (m, 2H), 6.98 (dd, 1H), 6.76 (sept, 1H), 4.05 (q,2H), 3.51 (t, 2H), 2.66 (m, 2H); MS (m/z) 380.

Example 46N-(4-chlorophenyl)-1-pyrimidin-2-yl-1,2,3,6-tetrahydropyridine-4-carboxamideExample 46A 1-pyrimidin-2-yl-1,2,3,6-tetrahydropyridine-4-carboxylicacid

2-Chloropyrimidine (0.570 g, 4.98 mmol) and1,2,3,6-tetrahydro-4-pyridinecarboxylic acid (1.22 g) were combined inwater (7 mL) and heated at 90° C. After 4 hours, the mixture was treatedwith additional 1,2,3,6-tetrahydro-4-pyridinecarboxylic acid (0.52 g)and stirred overnight. The mixture was diluted with water and extractedwith CH₂Cl₂. The aqueous layer was acidified with concentrated HCl(pH˜3) and extracted with CHCl₃. The organic layer was dried (Na₂SO₄),filtered, and the filtrate was concentrated under reduced pressure toprovide the title.

Example 46BN-(4-chlorophenyl)-1-pyrimidin-2-yl-1,2,3,6-tetrahydropyridine-4-carboxamide

1-Pyrimidin-2-yl-1,2,3,6-tetrahydropyridine-4-carboxylic acid (55.0 mg,0.27 mmol) and a catalytic amount of DMF were combined in CH₂Cl₂ (1.5mL) and treated with (COCl)₂ (0.033 mL, 0.38 mmol). The mixture wasstirred for 90 minutes, diluted with toluene (0.5 mL), and concentratedto dryness under reduced pressure. The residue in CH₂Cl₂ (1.5 mL) wastreated with pyridine (0.033 mL, 0.41 mmol), catalytic amount of DMAP,and 4-chloroaniline (41.0 mg, 0.32 mmol). The mixture was stirred for 1hour, diluted with water, and extracted with CH₂Cl₂. The organic phasewas dried (Na₂SO₄), filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography (15%ethyl acetate/CH₂Cl₂) to provide the title compound. ¹H NMR (300 MHz,CDCl₃) δ 8.35 (d, 2H), 7.51 (d, 2H), 7.39 (brs, 1H), 7.31 (d, 2H), 6.77(sept, 1H), 6.54 (t, 1H), 4.43 (q, 2H), 4.03 (t, 2H), 2.58 (m, 2H); MS(m/z) 315.

Example 471-pyrimidin-2-yl-N-{4-[(trifluoromethyl)thio]phenyl}-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was prepared using the procedure described in Example46B using 4-[(trifluoromethyl)thio]aniline instead of 4-chloroaniline.¹H NMR (300 MHz, CDCl₃) δ 8.35 (d, 2H), 7.64 (s, 4H), 7.50 brs, 1H),6.78 (sept, 1H), 6.56 (t, 1H), 4.45 (q, 2H), 4.05 (t, 2H), 2.59 (m, 2H);MS (m/z) 381.

Example 481-pyrimidin-2-yl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was prepared using the procedure described in Example46B using 4-[(trifluoromethyl)sulfonyl]aniline instead of4-chloroaniline. ¹H NMR (300 MHz, CDCl₃) δ 8.36 (d, 2H), 8.00 (d, 2H),7.90 (d, 2H), 7.72 (brs, 1H), 6.84 (m, 1H), 6.57 (t, 1H), 4.48 (q, 2H),4.06 (t, 2H), 2.61 (m, 2H); MS (m/z) 413.

The foregoing is merely illustrative and is not intended to limit theinvention to the disclosed compounds. Variations and changes which areobvious to one skilled in the art are to be within the scope and natureof the invention which are defined in the appended claims.

Example 493′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-tert-butyl-phenyl)-amide Example 49A3′-Trifluoromethyl-2,3,5,6-tetrahydro-[1,2′]bipyridinyl-4-one

A suspension of K₂CO₃ (19.10 g, 138 mmol),2-chloro-3-(trifluoromethyl)pyridine (11.92 g, 65.7 mmol)) and1,4-Dioxa-8-aza-spiro[4.5]decane (8.85 mL, 69.0 mmol) in DMSO (65 mL)was stirred at 100° C. for 3 hour. Additional1,4-Dioxa-8-aza-spiro[4.5]decane (2.0 mL, 16 mmol) was added and stirredfor an additional 2 hour, followed by another aliquot (1.0 mL, 7.8 mmol)and stirring for 1 hour. The mixture was diluted with Et₂O (200 mL), andwashed with water (250 mL), washed with brine (100 mL), and the organiclayer dried (Na₂SO₄), filtered and concentrated under reduced pressure.The residue was then dissolved in conc HCl (25 mL), stirred 3 hour,basified with conc NH₄OH, extracted with CH₂Cl₂, and dried (Na₂SO₄), andconcentrated. Flash chromatographic purification (20 to 40% Et₂O/Hexgradient elution) provided the substituted piperidone as a yellow solid(8.35 g, 34.2 mmol, 52%): ¹H NMR (300 MHz, CDC₃l) δ 8.46 (d, J=4.6 Hz,1H), 7.92 (d, J=7.6 Hz, 1H), 7.07 (dd, J=4.6, 7.6 Hz, 1H), 3.59 (t,J=5.9 Hz, 4H), 2.61 (t, J=5.9 Hz, 4H).

Example 49B3′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acidmethyl ester

A solution of the piperidone (8.30 g, 34.0 mmol) in THF (25 mL) wasadded to a solution of LDA (lithium diisopropylamine) (37.3 mmol) in THF(75 mL) at −78° C., and stirred 45 minutes. Solid PhNTf₂ (14.0 g, 39.1mmol) was then added, and stirred for 1 hour. The mixture wasconcentrated under reduced pressure and diluted with 1:1 EtOAc:hexane,and washed with 1 N NaOH. The organic layer was dried (Na₂SO₄), andfiltered through a silica plug, and concentrated under reduced pressureto provide 14.4 g of a red oil. This residue and Et₃N (14.2 mL, 102mmol) and MeOH (7.00 mL, 173 mmol) were dissolved in DMF (100 mL), andsaturated with CO (bubbling 15 minutes). Solid PdCl₂(PPh₃)₂ (0.944 g,1.34 mmol) was added, and the mixture was heated to 80° C. under CO (1atm) overnight. The mixture was then concentrated under reduced pressureto half volume, diluted with Et₂O, washed with water, brine, dried(Na₂SO₄), concentrated under reduced pressure and purified by flashchromatography (6% EtOAc/hexane) to provide the methyl ester as a yellowsolid (3.90 g, 13.6 mmol, 40%): ¹H NMR (300 MHz, CDCl₃) δ 8.40 (dd,J=1.7, 4.8 Hz, 1H), 7.87 (dd, J=1.7, 7.8 Hz, 1H), 7.01 (sept, J=1.7 Hz,1H), 6.96 (ddd, J=1.0, 4.8, 7.8 Hz, 1H), 4.03 (q, J=3.0 Hz, 2H), 3.77(s, 3H), 3.44 (t, J=5.4 Hz, 2H).

Example 49C3′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid

The ester was dissolved in MeOH (15 mL) and THF (30 mL), and stirredwith 1 N NaOH (27 mL) for 2 hour. Additional 1 N NaOH (16 mL) was addedand stirred for 1 hour, followed by another aliquot (14.5 mL) for 1hour. The mixture was then diluted with water, and extracted withCH₂Cl₂. The aqueous layer was then acidified with conc HCl and extractedwith CHCl₃. The organic layer was dried (Na₂SO₄) and concentrated underreduced pressure to provide 13c a tan solid (3.00 g, 11.0 mmol, 81%): ¹HNMR (300 MHz, CD₃OD) δ 8.45 (m, 1H), 7.99 (dd, J=2.4, 7.8 Hz, 1H), 7.11(m, 1H), 7.02 (sept, J=1.7 Hz, 1H), 3.99 (q, J=3.1 Hz, 2H), 3.39 (t,J=5.6 Hz, 2H), 2.49 (m, 2H).

Example 49D3′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-tert-butyl-phenyl)-amide

To a suspension of3′-trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(60.4 mg, 0.194 mmol) and DMF (cat) in CH₂Cl₂ (1 mL) was added (COCl)₂(0.027 mL, 0.31 mmol). The mixture was stirred for 90 minutes, dilutedwith PhMe (0.5 mL), concentrated under reduced pressure to dryness, anddissolved in CH₂Cl₂ (1.5 mL). To the solution were added pyridine (0.027mL, 0.33 mmol), DMAP (cat), and 4-tert-butylaniline (0.037 mL, 0.023mmol). The mixture was stirred 1 hour, diluted with water and extractedwith CH₂Cl₂, dried (Na₂SO₄), and purified by flash chromatography (7%EtOAc/CH₂Cl₂) to provide as a white solid (54.2 mg, 0.123 mmol, 63%):

MS (ESI+) m/z 404 (M+H)⁺, m/z 402 (M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D)δ ppm 1.31 (s, 9H), 2.67 (m, 2H), 3.53 (t, J=5.4 Hz, 2H), 4.07 (q, J=2.9Hz, 2H), 6.76 (m, 1H), 6.98 (dd, J=7.5, 4.4 Hz, 1H), 7.36 (m, 3H), 7.48(m, 2H), 7.89 (dd, J=7.8, 1.7 Hz, 1H), 8.42 (dd, J=4.7, 1.4 Hz, 1H).

Example 50 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-azepan-1-yl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-Azepan-1-yl-phenylamine instead of 4-tert-butylaniline. MS(ESI+) m/z 411 (M+H)⁺, m/z 409 (M−H)⁻; 1H NMR (500 MHz, CHLOROFORM-D) δppm 1.82 (s, 4H), 2.09 (s, 4H), 2.71 (d, J=1.6 Hz, 2H), 3.63 (m, 4H),3.76 (t, J=5.6 Hz, 2H), 4.25 (d, J=2.8 Hz, 2H), 6.77 (s, 1H), 7.01 (dd,J=7.8, 5.3 Hz, 1H), 7.46 (d, J=9.0 Hz, 2H), 7.74 (d, J=9.0 Hz, 2H), 7.87(dd, J=7.8, 1.6 Hz, 1H), 8.20 (dd, J=5.3, 1.6 Hz, 1H), 8.59 (s, 1H).

Example 51 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(1-tert-butyl-1H-pyrazol-4-yl)-amide

The title compound was prepared using the procedure described in Example49D using 4-1-tert-butyl-1H-pyrazol-4-ylamine instead of4-tert-butylaniline. ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.50 (s, 9H), 2.53(s, 2H), 3.45 (t, J=5.6 Hz, 2H), 3.99 (q, J=2.7 Hz, 2H), 6.74 (s, 1H),7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.53 (s, 1H), 7.82 (dd, J=7.8, 1.7 Hz,1H), 7.99 (s, 1H), 8.22 (m, 1H), 9.85 (s, 1H).

Example 52 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-tert-butyl-phenyl)-amide Example 52A1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid

A mixture of 2-chloropyrimidine (0.570 g, 4.98 mmol), and isoguvacine,sodium salt (1.2 g, 8.2 mmol) in water (7 mL) was heated to 90° C. andstirred for 4 hour. Additional isoguvacine, sodium salt (0.52 g, 3.3mmol) was then added and stirred overnight. The mixture was diluted withwater and extracted with CH₂Cl₂. The aqueous layer was acidified withconc HCl (pH˜3) and extracted with CHCl₃. The organic layer was dried(Na₂SO₄), filtered and concentrated under reduced pressure to provide1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid a whitesolid (0.564 g, 2.75 mmol, 55%): ¹H NMR (300 MHz, CD₃OD) δ 8.43 (d,J=4.8 Hz, 2H), 7.02 (sept, J=1.7 Hz, 1H), 6.74 (t, J=4.8 Hz, 1H), 4.39(q, J=3.0 Hz, 2H), 3.97 (t, J=5.8 Hz, 2H), 2.49 (m, 2H).

Example 52B 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-tert-butyl-phenyl)-amide

To a suspension of1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid (60.4 mg,0.194 mmol) and DMF (cat) in CH₂Cl₂ (1 mL) was added (COCl)₂ (0.027 mL,0.31 mmol). The mixture was stirred for 90 minutes, diluted with PhMe(0.5 mL), concentrated under reduced pressure to dryness, and dissolvedin CH₂Cl₂ (1.5 mL). To the solution were added pyridine (0.027 mL, 0.33mmol), DMAP (cat), and 4-tert-butylaniline (0.037 mL, 0.023 mmol). Themixture was stirred 1 hour, diluted with water and extracted withCH₂Cl₂, dried (Na₂SO₄), and purified by flash chromatography (7%EtOAc/CH₂Cl₂) to provide1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid(4-tert-butyl-phenyl)-amide as a white solid (54.2 mg, 0.123 mmol, 63%):MS (ESI+) m/z 337 (M+H)⁺, m/z 334 (M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D)δ ppm 1.31 (s, 9H), 2.59 (m, 2H), 4.04 (t, J=5.6 Hz, 2H), 4.44 (q, J=3.1Hz, 2H), 6.54 (t, J=4.7 Hz, 1H), 6.75 (m, 1H), 7.36 (m, 3H), 7.47 (m,2H), 8.35 (d, J=4.7 Hz, 2H).

Example 53 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-chloro-phenyl)-amide

The title compound was prepared using the procedure described in Example52B using 4-chloro-aniline instead of 4-ter-butylaniline. MS (ESI+) m/z315 (M+H)⁺; 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.58 (m, 2H), 4.03 (t,J=5.6 Hz, 2H), 4.44 (q, J=3.1 Hz, 2H), 6.54 (t, J=4.7 Hz, 1H), 6.77 (m,1H), 7.30 (d, J=9.2 Hz, 2H), 7.39 (s, 1H), 7.52 (d, J=8.8 Hz, 2H), 8.35(d, J=4.7 Hz, 2H).

Example 54 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-trifluoromethyoxy-phenyl)-amide

The title compound was prepared using the procedure described in Example52B using 4-trifluoromethoxy-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 365 (M+H)⁺, m/z 363 (M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D) δppm 2.59 (m, 2H), 4.04 (t, J=5.6 Hz, 2H), 4.44 (q, J=3.1 Hz, 2H), 6.55(t, J=4.7 Hz, 1H), 6.77 (m, 1H), 7.19 (d, J=9.2 Hz, 2H), 7.44 (s, 1H),7.59 (d, J=9.2 Hz, 2H), 8.35 (d, J=4.7 Hz, 2H).

Example 55 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-trifluoromethylsulfanyl-phenyl)-amide

The title compound was prepared using the procedure described in Example52B using 4-trifluoromethylsulfanyl-aniline instead of4-ter-butylaniline. MS (ESI+) m/z 381 (M+H)⁺, m/z 379 (M−H)⁻; 1H NMR(300 MHz, DMSO-D6) δ ppm 2.47 (s, 2H), 3.93 (t, J=5.8 Hz, 2H), 4.38 (q,J=2.7 Hz, 2H), 6.69 (t, J=4.7 Hz, 1H), 6.84 (m, 1H), 7.66 (d, J=8.8 Hz,2H), 7.86 (d, J=8.8 Hz, 2H), 8.42 (d, J=5.1 Hz, 2H), 10.09 (s, 1H).

Example 56 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-trifluoromethanesulfonyl-phenyl)-amide

The title compound was prepared using the procedure described in Example52B using 4-trifluoromethylsulfonyl-aniline instead of4-ter-butylaniline. MS (ESI+) m/z 413 (M+H)⁺, m/z 411 (M−H)⁻; 1H NMR(300 MHz, CHLOROFORM-D) δ ppm 2.61 (s, 2H), 4.06 (t, J=5.6 Hz, 2H), 4.49(q, J=2.9 Hz, 2H), 6.57 (t, J=4.7 Hz, 1H), 6.84 (s, 1H), 7.72 (s, 1H),7.89 (d, J=8.8 Hz, 2H), 8.01 (d, J=8.8 Hz, 2H), 8.36 (d, J=4.7 Hz, 2H).

Example 57 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-bromo-3-fluoro-phenyl)-amide

The title compound was prepared using the procedure described in Example52B using 4-bromo-3-fluoro-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 411 (M+H)⁺, m/z 409 (M−H)⁻; 1H NMR (300 MHz, DMSO-D6) δ ppm2.55 (d, J=1.7 Hz, 2H), 3.45 (t, J=5.6 Hz, 2H), 4.02 (q, J=2.9 Hz, 2H),6.82 (s, 1H), 7.01 (dd, J=7.8, 4.7 Hz, 1H), 7.47 (dd, J=8.8, 2.4 Hz,1H), 7.63 (t, J=8.8 Hz, 1H), 7.82 (d, J=1.4 Hz, 1H), 7.85 (dd, J=4.9,1.9 Hz, 1H), 8.22 (dd, J=4.7, 1.7 Hz, 1H), 10.05 (s, 1H).

Example 58 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-bromo-3-methyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-bromo-3-methyl-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 407 (M+H)⁺, m/z 405 (M−H)⁻; 1H NMR (300 MHz, DMSO-D6) δ ppm2.32 (s, 3H), 2.56 (s, 2H), 3.44 (t, J=5.4 Hz, 2H), 4.01 (q, J=2.7 Hz,2H), 6.79 (s, 1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.49 (s, 2H), 7.71 (s,1H), 7.83 (dd, J=7.6, 1.5 Hz, 1H), 8.22 (dd, J=4.7, 1.7 Hz, 1H), 9.78(s, 1H).

Example 593′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-chloro-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-chloro-aniline instead of 4-ter-butylaniline. MS (ESI+) m/z382 (M+H)⁺, m/z 380 (M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.66(m, 2H), 3.51 (t, J=5.6 Hz, 2H), 4.06 (q, J=3.1 Hz, 2H), 6.77 (m, 1H),6.99 (dd, J=8.1, 4.4 Hz, 1H), 7.30 (m, 2H), 7.43 (s, 1H), 7.52 (m, 2H),7.89 (dd, J=7.8, 1.7 Hz, 1H), 8.42 (dd, J=4.7, 1.4 Hz, 1H).

Example 603′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-trifluoromethoxy-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-trifluoromethoxy-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 432 (M+H)⁺, m/z 430 (M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D) δppm 2.67 (m, 2H), 3.53 (t, J=5.4 Hz, 2H), 4.08 (q, J=2.7 Hz, 2H), 6.79(s, 1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.20 (d, J=8.1 Hz, 2H), 7.48 (s,1H), 7.60 (d, J=9.2 Hz, 2H), 7.90 (dd, J=7.8, 1.7 Hz, 1H), 8.43 (dd,J=4.9, 1.2 Hz, 1H).

Example 613′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-trifluoromethylsulfanyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-trifluoromethylsulfanyl-aniline instead of4-ter-butylaniline. MS (ESI+) m/z 448 (M+H)⁺, m/z 446 (M−H)⁻; 1H NMR(300 MHz, CHLOROFORM-D) δ ppm 2.66 (m, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.08(q, J=2.8 Hz, 2H), 6.79 (m, 1H), 7.01 (dd, J=7.8, 4.7 Hz, 1H), 7.53 (s,1H), 7.64 (d, J=2.4 Hz, 4H), 7.90 (dd, J=7.8, 1.7 Hz, 1H), 8.43 (d,J=3.4 Hz, 1H).

Example 62 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-bromo-3-chloro-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-bromo-3-chloro-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 427 (M+H)⁺, m/z 425 (M−H)⁻; 1H NMR (300 MHz, DMSO-D6) δ ppm2.55 (m, 2H), 3.45 (t, J=5.6 Hz, 2H), 4.02 (q, J=2.7 Hz, 2H), 6.83 (m,1H), 7.01 (dd, J=7.8, 4.7 Hz, 1H), 7.60 (m, 1H), 7.70 (m, 1H), 7.83 (dd,J=7.8, 1.7 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H), 8.22 (dd, J=4.7, 1.7 Hz,1H), 10.00 (s, 1H).

Example 633′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-azepan-1-yl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-azepan-1-yl-aniline instead of 4-ter-butylaniline. MS (ESI+)m/z 445 (M+H)⁺, m/z 443 (M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D) δ ppm1.54 (m, 4H), 1.78 (s, 4H), 2.65 (m, 2H), 3.44 (s, 4H), 3.52 (t, J=5.4Hz, 2H), 4.05 (d, J=2.4 Hz, 2H), 6.65 (d, J=5.8 Hz, 2H), 6.73 (s, 1H),6.97 (dd, J=7.8, 4.7 Hz, 1H), 7.22 (m, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.87(dd, J=7.8, 2.0 Hz, 1H), 8.41 (dd, J=4.7, 1.7 Hz, 1H).

Example 64 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-bromo-3-trifluoromethyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-bromo-3-trifluoromethyl-aniline instead of4-ter-butylaniline. MS (ESI+) m/z 461 (M+H)⁺, m/z 459 (M−H)⁻; 1H NMR(300 MHz, DMSO-D6) δ ppm 2.56 (br. s, 2H), 3.46 (t, J=5.6 Hz, 2H), 4.03(q, J=2.7 Hz, 2H), 6.86 (m, 1H), 7.01 (dd, J=7.8, 4.7 Hz, 1H), 7.82 (d,J=1.7 Hz, 1H), 7.84 (m, 1H), 7.95 (dd, J=8.8, 2.4 Hz, 1H), 8.23 (dd,J=4.7, 1.7 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 10.14 (s, 1H).

Example 65 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-chloro-3-fluoro-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-chloro-3-fluoro-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 365 (M+H)⁺, m/z 363 (M−H)⁻; 1H NMR (300 MHz, DMSO-D6) δ ppm2.55 (br. s, 2H), 4.02 (q, J=2.9 Hz, 2H), 6.82 (m, 1H), 7.01 (dd, J=7.8,4.7 Hz, 1H), 7.52 (m, 2H), 7.84 (m, 2H), 8.22 (dd, J=4.7, 1.7 Hz, 1H),10.05 (s, 1H).

Example 66 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(3,4-dichloro-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 3,4-dichloro-aniline instead of 4-ter-butylaniline. MS (ESI+)m/z 381 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.55 (m, 2H), 3.45 (t,J=5.4 Hz, 2H), 4.02 (q, J=2.8 Hz, 2H), 6.82 (m, 1H), 7.01 (dd, J=7.8,4.7 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.67 (dd, J=8.8, 2.4 Hz, 1H), 7.83(dd, J=7.8, 1.7 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H), 8.22 (dd, J=4.7, 1.7Hz, 1H), 10.01 (s, 1H).

Example 67 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-chloro-3-methyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-chloro-3-methyl-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 361 (M+H)⁺, m/z 360 (M−H)⁻; 1H NMR (300 MHz, DMSO-D6) δ ppm2.30 (s, 3H), 2.55 (m, 2H), 3.46 (t, J=5.4 Hz, 2H), 4.01 (q, J=2.7 Hz,2H), 6.79 (m, 1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H),7.55 (dd, J=8.6, 2.5 Hz, 1H), 7.70 (d, J=2.7 Hz, 1H), 7.83 (dd, J=7.8,1.4 Hz, 1H), 8.22 (dd, J=4.7, 1.7 Hz, 1H), 9.78 (s, 1H).

Example 68 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-chloro-3-trifluoromethyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-chloro-3-trifluoromethyl-aniline instead of4-ter-butylaniline. MS (ESI+) m/z 415 (M+H)⁺, m/z 413 (M−H)⁻; 1H NMR(300 MHz, DMSO-D6) δ ppm 2.56 (m, 2H), 3.46 (t, J=5.6 Hz, 2H), 4.03 (q,J=2.7 Hz, 2H), 6.86 (m, 1H), 7.01 (dd, J=7.8, 4.7 Hz, 1H), 7.67 (d,J=8.8 Hz, 1H), 7.83 (dd, J=7.8, 1.7 Hz, 1H), 8.02 (dd, J=8.8, 2.7 Hz,1H), 8.22 (dd, J=4.6, 1.5 Hz, 1H), 8.28 (d, J=2.7 Hz, 1H), 10.14 (s,1H).

Example 69 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-difluoromethyoxy-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-difluoromethyoxy-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 379 (M+H)⁺, m/z 377 (M−H)⁻; 1H NMR (300 MHz, DMSO-D6) δ ppm2.56 (m, 2H), 3.45 (t, J=5.8 Hz, 2H), 4.02 (q, J=2.7 Hz, 2H), 6.79 (m,1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.13 (d, J=8.1 Hz, 2H), 7.15 (t, J=45Hz, 1H), 7.72 (d, J=9.2 Hz, 2H), 7.83 (dd, J=7.8, 1.7 Hz, 1H), 8.22 (dd,J=4.7, 1.4 Hz, 1H), 9.82 (s, 1H).

Example 70 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-amide

The title compound was prepared using the procedure described in Example49D using 4-(1,1,2,2-tetrafluoro-ethoxy)-aniline instead of4-ter-butylaniline. MS (ESI+) m/z 429 (M+H)⁺, m/z 427 (M−H)⁻; 1H NMR(300 MHz, DMSO-D6) δ ppm 2.56 (m, 2H), 3.46 (t, J=5.6 Hz, 2H), 4.02 (q,J=2.7 Hz, 2H), 6.79 (m, 1H), 6.80 (tt, J=52, 3.1 Hz, 1H), 7.01 (dd,J=7.6, 4.6 Hz, 1H), 7.23 (d, J=9.2 Hz, 2H), 7.78 (d, J=9.2 Hz, 2H), 7.83(dd, J=7.8, 1.7 Hz, 1H), 8.23 (dd, J=4.7, 1.7 Hz, 1H), 9.90 (s, 1H).

Example 71 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(3-chloro-4-methyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 3-chloro-4-methyl-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 361 (M+H)⁺, m/z 360 (M−H)⁻; 1H NMR (300 MHz, DMSO-D6) δ ppm2.28 (s, 3H), 2.55 (m, 2H), 3.45 (t, J=5.6 Hz, 2H), 4.01 (q, J=2.8 Hz,2H), 6.79 (m, 1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H),7.52 (dd, J=8.3, 2.2 Hz, 1H), 7.83 (dd, J=7.5, 1.4 Hz, 1H), 7.86 (d,J=2.0 Hz, 1H), 8.22 (dd, J=4.7, 1.7 Hz, 1H), 9.81 (s, 1H).

Example 72 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(3-bromo-4-methyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 3-bromo-4-methyl-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 407 (M+H)⁺, m/z 405 (M−H)⁻; 1H NMR (300 MHz, DMSO-D6) δ ppm2.29 (s, 3H), 2.55 (m, 2H), 3.45 (t, J=5.4 Hz, 2H), 4.01 (q, J=2.7 Hz,2H), 6.79 (m, 1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.28 (d, J=9.2 Hz, 1H),7.58 (dd, J=8.3, 2.2 Hz, 1H), 7.82 (dd, J=7.8, 1.4 Hz, 1H), 8.03 (d,J=2.0 Hz, 1H), 8.22 (dd, J=4.7, 1.4 Hz, 1H), 9.80 (s, 1H).

Example 73 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-methyl-3-trifluoromethyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 3-trifluoromethyl-4-methyl-aniline instead of4-ter-butylaniline. MS (ESI+) m/z 396 (M+H)⁺, m/z 394 (M−H)⁻; 1H NMR(300 MHz, DMSO-D6) δ ppm 2.39 (d, J=1.7 Hz, 3H), 2.56 (m, 2H), 3.46 (t,J=5.6 Hz, 2H), 4.02 (q, J=2.7 Hz, 2H), 6.83 (m, 1H), 7.00 (dd, J=7.8,4.7 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.84 (m, 2H), 8.09 (d, J=2.4 Hz,1H), 8.22 (dd, J=4.6, 1.5 Hz, 1H), 9.94 (s, 1H).

Example 74 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(5-fluoro-pyridin-2-yl)-amide

The title compound was prepared using the procedure described in Example49D using 5-fluoro-pyridin-2-ylamine instead of 4-ter-butylaniline. MS(ESI+) m/z 330 (M−H)⁻ (20%) m/z 212 (M−120)⁻ (100%); 1H NMR (300 MHz,DMSO-D6) δ ppm 2.57 (m, 2H), 4.00 (q, J=2.8 Hz, 3H), 6.92 (m, 1H), 7.00(dd, J=7.8, 4.7 Hz, 1H), 7.75 (m, 1H), 7.82 (dd, J=7.8, 1.7 Hz, 1H),8.11 (dd, J=9.3, 4.2 Hz, 1H), 8.22 (dd, J=4.7, 1.7 Hz, 1H), 8.35 (d,J=3.4 Hz, 1H), 10.30 (s, 1H).

Example 75 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(5-chloro-pyridin-2-yl)-amide

The title compound was prepared using the procedure described in Example49D using 5-chloro-pyridin-2-ylamine instead of 4-ter-butylaniline. MS(ESI+) m/z 348 (M+H)⁺, m/z 346 (M−H)⁻ (80%) m/z 212 (M−137)⁻ (100%); 1HNMR (300 MHz, DMSO-D6) δ ppm 2.57 (m, 2H), 3.44 (t, J=5.4 Hz, 2H), 4.00(q, J=2.9 Hz, 2H), 6.94 (m, 1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.82 (dd,J=7.8, 1.7 Hz, 1H), 7.91 (dd, J=9.0, 2.9 Hz, 1H), 8.11 (d, J=0.7 Hz,1H), 8.22 (dd, J=4.7, 1.4 Hz, 1H), 8.40 (dd, J=2.5, 0.8 Hz, 1H), 10.39(s, 1H).

Example 76 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(5-bromo-pyridin-2-yl)-amide

The title compound was prepared using the procedure described in Example49D using 5-bromo-pyridin-2-ylamine instead of 4-ter-butylaniline. MS(ESI+) m/z 395 (M+H)⁺ (60%), m/z 392 (M−H)⁺ (100%), m/z 392 (M−H)⁻; 1HNMR (300 MHz, DMSO-D6) δ ppm 2.56 (m, 2H), 3.44 (t, J=5.6 Hz, 2H), 4.00(q, J=2.7 Hz, 2H), 6.95 (m, 1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.82 (dd,J=7.8, 1.7 Hz, 1H), 8.04 (m, 2H), 8.22 (dd, J=4.7, 1.7 Hz, 1H), 8.47(dd, J=2.4, 0.7 Hz, 1H), 10.39 (s, 1H).

Example 77 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(5-iodo-pyridin-2-yl)-amide

The title compound was prepared using the procedure described in Example49D using 5-iodo-pyridin-2-ylamine instead of 4-ter-butylaniline. MS(ESI+) m/z 441 (M+H)⁺ (95%), m/z 436 (M−4)⁺ (100%), m/z 438 (M−H)⁻(25%), m/z 211 (M−229)⁻ (100%); 1H NMR (300 MHz, DMSO-D6) δ ppm 2.56 (m,2H), 3.99 (q, J=2.7 Hz, 2H), 6.94 (m, 1H), 7.00 (dd, J=7.6, 4.6 Hz, 1H),7.82 (dd, J=7.8, 1.7 Hz, 1H), 7.97 (dd, J=8.8, 1.0 Hz, 1H), 8.12 (dd,J=8.6, 2.2 Hz, 1H), 8.21 (dd, J=4.6, 1.5 Hz, 1H), 8.56 (dd, J=2.4, 0.7Hz, 1H), 10.33 (s, 1H).

Example 78 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-trifluoromethylsulfanyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 5-fluoro-pyridin-2-ylamine instead of 4-ter-butylaniline. MS(ESI+) m/z 413 (M+H)⁺, m/z 411 (M−H)⁻; 1H NMR (400 MHz, DMSO-D6) δ ppm2.57 (m, 2H), 3.46 (t, J=5.5 Hz, 2H), 4.03 (q, J=2.9 Hz, 2H), 6.84 (m,1H), 7.00 (dd, J=7.7, 4.6 Hz, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.82 (dd,J=7.8, 1.7 Hz, 1H), 7.87 (m, 2H), 8.23 (dd, J=4.8, 1.7 Hz, 1H), 10.04(s, 1H).

Example 79 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(3-fluoro-4-trifluoromethyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 3-fluoro-4-trifluoromethyl-aniline instead of4-ter-butylaniline. MS (DCI+) m/z 400 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6)δ ppm 2.57 (m, 2H), 3.46 (t, J=5.4 Hz, 2H), 4.04 (q, J=3.1 Hz, 2H), 6.88(m, 1H), 7.01 (dd, J=7.6, 4.6 Hz, 1H), 7.70 (m, 2H), 7.83 (dd, J=7.8,1.7 Hz, 1H), 7.91 (d, J=13.6 Hz, 1H), 8.23 (dd, J=4.7, 1.4 Hz, 1H),10.28 (s, 1H).

Example 80 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-bromo-2-chloro-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 2-chloro-4-bromo-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 427 (M+H)⁺ (80%), m/z 459 (M+32)⁺ (100%), m/z 426 (M−H)⁻(90%), m/z 305 (M−122)⁻ (100%); 1H NMR (400 MHz, DMSO-D6) δ ppm 2.56 (m,2H), 3.46 (t, J=5.5 Hz, 2H), 4.03 (q, J=2.8 Hz, 2H), 6.89 (m, 1H), 7.00(dd, J=7.8, 4.8 Hz, 1H), 7.55 (m, 2H), 7.79 (d, J=1.8 Hz, 1H), 7.82 (dd,J=7.7, 1.8 Hz, 1H), 8.22 (dd, J=4.8, 1.4 Hz, 1H), 9.45 (s, 1H).

Example 81 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-bromo-2-fluoro-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 2-fluoro-4-bromo-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 410 (M+H)⁺ (80%), m/z 407 (M−3)⁺ (100%), m/z 409 (M−H)⁻; 1HNMR (400 MHz, DMSO-D6) δ ppm 2.55 (m, 2H), 3.46 (t, J=5.5 Hz, 2H), 4.02(q, J=3.0 Hz, 2H), 6.86 (m, 1H), 7.00 (dd, J=7.8, 4.8 Hz, 1H), 7.40 (dd,J=8.6, 1.2 Hz, 1H), 7.54 (t, J=8.4 Hz, 1H), 7.59 (dd, J=10.1, 2.1 Hz,1H), 7.82 (dd, J=7.8, 1.7 Hz, 1H), 8.22 (dd, J=4.6, 1.5 Hz, 1H), 9.60(s, 1H).

Example 82 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-bromo-2-methyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 2-methyl-4-bromo-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 407 (M+H)⁺, m/z 405 (M−H)⁻; 1H NMR (400 MHz, DMSO-D6) δ ppm2.19 (s, 3H), 2.57 (m, 2H), 3.46 (t, J=5.5 Hz, 2H), 4.02 (q, J=2.9 Hz,2H), 6.83 (m, 1H), 7.00 (dd, J=7.8, 4.8 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H),7.36 (m, 1H), 7.46 (d, J=1.5 Hz, 1H), 7.82 (dd, J=7.8, 1.7 Hz, 1H), 8.22(dd, J=4.8, 1.7 Hz, 1H), 9.30 (s, 1H).

Example 83 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(2-fluoro-4-iodo-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 2-fluoro-4-iodo-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 457 (M+H)⁺ (80%), m/z 453 (M−4)⁺ (100%), m/z 455 (M−H)⁻; 1HNMR (400 MHz, DMSO-D6) δ ppm 2.54 (m, 2H), 3.46 (t, J=5.5 Hz, 2H), 4.01(q, J=2.8 Hz, 2H), 6.85 (m, 1H), 7.00 (dd, J=7.7, 4.6 Hz, 1H), 7.38 (t,J=8.3 Hz, 1H), 7.54 (dd, J=8.3, 1.2 Hz, 1H), 7.68 (dd, J=10.0, 2.0 Hz,1H), 7.82 (dd, J=8.0, 1.5 Hz, 1H), 8.22 (dd, J=4.6, 1.5 Hz, 1H), 9.57(s, 1H).

Example 84 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-chloro-2-trifluoromethyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 2-trifluoromethyl-4-chloro-aniline instead of4-ter-butylaniline. MS (ESI+) m/z 417 (M+H)⁺ (75%), m/z 230 (M−186)⁺(100%), m/z 414 (M−H)⁻; 1H NMR (400 MHz, DMSO-D6) δ ppm 2.54 (m, 2H),3.46 (t, J=5.4 Hz, 2H), 4.02 (q, J=2.8 Hz, 2H), 6.83 (m, 1H), 7.00 (dd,J=7.8, 4.8 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 7.78 (dd, J=8.6, 2.5 Hz,1H), 7.82 (m, 2H), 8.22 (dd, J=4.8, 1.7 Hz, 1H), 9.57 (s, 1H).

Example 85 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-chloro-2-fluoro-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 2-fluoro-4-chloro-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 366 (M+H)⁺, m/z 365 (M−H)⁻ (80%), m/z 363 (M−3)⁻ (100%); 1HNMR (400 MHz, DMSO-D6) δ ppm 2.55 (m, 2H), 3.46 (t, J=5.5 Hz, 2H), 4.02(q, J=2.8 Hz, 2H), 6.86 (m, 1H), 7.00 (dd, J=7.7, 4.6 Hz, 1H), 7.28 (m,1H), 7.49 (dd, J=10.4, 2.5 Hz, 1H), 7.58 (t, J=8.4 Hz, 1H), 7.82 (dd,J=7.8, 1.7 Hz, 1H), 8.22 (d, J=1.5 Hz, 1H), 9.60 (s, 1H).

Example 86 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(2,2-difluoro-benzo[1,3]dioxol-5-yl)-amide

The title compound was prepared using the procedure described in Example49D using 2,2-difluoro-benzo[1,3]dioxol-5-yl amine instead of4-ter-butylaniline. MS (ESI+) m/z 216 (M−177)⁺ (100%), m/z 391 (M−H)⁻;1H NMR (300 MHz, DMSO-D6) δ ppm 2.56 (m, 2H), 3.46 (t, J=5.6 Hz, 2H),4.02 (q, J=2.7 Hz, 2H), 6.80 (m, 1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.35(d, J=8.8 Hz, 1H), 7.42 (dd, J=8.8, 2.0 Hz, 1H), 7.83 (m, 2H), 8.22 (dd,J=4.7, 1.7 Hz, 1H), 9.94 (s, 1H).

Example 87 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(3,4-dimethyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 3,4-dimethyl-aniline instead of 4-ter-butylaniline. MS (ESI+)m/z 342 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.17 (s, 3H), 2.19 (s,3H), 2.55 (m, 2H), 3.46 (t, J=5.4 Hz, 2H), 4.00 (q, J=2.7 Hz, 2H), 6.75(m, 1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.04 (m, 1H), 7.39 (dd, J=8.0,2.2 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.82 (dd, J=7.8, 1.7 Hz, 1H), 8.22(dd, J=4.6, 1.5 Hz, 1H), 9.56 (s, 1H).

Example 88 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(6-trifluoromethyl-pyridin-3-yl)-amide

The title compound was prepared using the procedure described in Example49D using 6-trifluoromethyl-pyridin-3-ylamine instead of4-ter-butylaniline. MS (ESI+) m/z 383 (M+H)⁺, m/z 380 (M−H)⁻; 1H NMR(300 MHz, DMSO-D6) δ ppm 2.58 (m, 2H), 3.47 (t, J=5.6 Hz, 2H), 4.05 (q,J=2.8 Hz, 2H), 6.92 (m, 1H), 7.01 (dd, J=7.8, 4.7 Hz, 1H), 7.84 (dd,J=7.8, 1.7 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.23 (dd, J=4.7, 1.7 Hz,1H), 8.40 (dd, J=8.3, 2.2 Hz, 1H), 9.01 (d, J=2.4 Hz, 1H), 10.32 (s,1H).

Example 89 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-tert-butyl-2-fluoro-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-tert-butyl-2-fluoro-aniline instead of 4-ter-butylaniline.MS (ESI+) m/z 388 (M+H)⁺, m/z 386 (M−H)⁻; 1H NMR (500 MHz, DMSO-D6) δppm 1.28 (s, 9H), 2.55 (m, 2H), 3.46 (t, J=5.5 Hz, 2H), 4.02 (q, J=3.1Hz, 2H), 6.84 (m, 1H), 7.01 (dd, J=7.8, 4.7 Hz, 1H), 7.19 (dd, J=8.4,2.0 Hz, 1H), 7.24 (dd, J=12.8, 2.1 Hz, 1H), 7.42 (t, J=8.4 Hz, 1H), 7.84(dd, J=7.6, 1.5 Hz, 1H), 8.22 (dd, J=4.6, 1.5 Hz, 1H), 9.47 (s, 1H).

Example 90 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(6-chloro-pyridin-3-yl)-amide

The title compound was prepared using the procedure described in Example49D using 6-chloro-pyridin-3-ylamine instead of 4-ter-butylaniline. MS(ESI+) m/z 348 (M+H)⁺, m/z 346 (M−H)⁻; 1H NMR (300 MHz, DMSO-D6) δ ppm2.55 (m, 2H), 3.46 (t, J=5.6 Hz, 2H), 4.03 (q, J=2.7 Hz, 2H), 6.86 (m,1H), 7.01 (dd, J=7.8, 4.7 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.83 (dd,J=7.8, 1.4 Hz, 1H), 8.17 (dd, J=8.6, 2.9 Hz, 1H), 8.23 (dd, J=4.7, 1.7Hz, 1H), 8.71 (d, J=2.4 Hz, 1H), 10.09 (s, 1H).

Example 91 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-tert-butyl-3-fluoro-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-tert-butyl-3-fluoro-aniline instead of 4-ter-butylaniline.MS (ESI+) m/z 388 (M+H)⁺, m/z 386 (M−H)⁻; 1H NMR (300 MHz, DMSO-D6) δppm 1.32 (s, 9H), 2.56 (m, 2H), 3.45 (t, J=5.6 Hz, 2H), 4.02 (q, J=2.7Hz, 2H), 6.80 (m, 1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.25 (t, J=9.5 Hz,1H), 7.39 (dd, J=8.8, 2.4 Hz, 1H), 7.58 (dd, J=15.4, 2.2 Hz, 1H), 7.83(dd, J=7.6, 1.5 Hz, 1H), 8.22 (dd, J=4.7, 1.4 Hz, 1H), 9.85 (s, 1H).

Example 923′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(8-aza-bicyclo[3.2.1]oct-8-yl)-phenyl]-amide Example 92A8-Aza-bicyclo[3.2.1]octane

To a solution of 8-Methyl-8-aza-bicyclo[3.2.1]octane (19.5 g, 0.156 mol)in DCE (500 mL) at 0° C. was added 1-chloroethyl chloroformate (19.5 mL,0.179 mol) over 5 min. The mixture was heated to reflux for 4 h,concentrated, and filtered through silica (50% Et₂O/Hex). The residuewas then refluxed in MeOH (150 mL) for 45 min and concentrated underreduced pressure to provide 8-Aza-bicyclo[3.2.1]octane as a light yellowsolid (19.2 g, 0.130 mol, 83%) %):

¹H NMR (300 MHz, CDCl₃) δ 9.47 (brs, 2H), 4.03 (m, 2H), 2.18-2.33 (m,4H), 1.81-1.89 (m, 2H), 1.55-1.77 (m, 4H).

Example 92B 4-(8-Aza-bicyclo[3.2.1]oct-8-yl)-phenylamine

A mixture of 4-fluoro-nitrobenzene (0.72 mL, 6.8 mmol),8-Aza-bicyclo[3.2.1]octane (1.01 g, 6.82 mmol), and K₂CO₃ (1.87 g, 13.5g) in DMSO (7 mL) was heated to 110° C. and stirred for 3 hour. Themixture was diluted with Et₂O (60 mL) and washed with water (40 mL) andbrine (30 mL). The organic layer was dried (Na₂SO4), concentrated, andtriturated with hexane to provide 1.27 g of a yellow solid. A mixture ofthe solid, HCO₂NH₄ (1.45 g, 23.0 mmol), and 10% Pd/C (cat) in MeOH (20mL) was stirred overnight, filtered, and concentrated. The residue wasdiluted with sat. aq. NaHCO₃ (20 mL) and extracted with CH₂Cl₂ (3×10mL). The organic layer was dried (Na₂SO₄) and concentrated under reducedpressure to provide 4-(8-Aza-bicyclo[3.2.1]oct-8-yl)-phenylamine as adark solid.

¹H NMR (300 MHz, CDCl₃) δ 6.66 (s, 4H), 4.07 (brs, 2H), 3.14 (brs, 2H),1.74-2.09 (m, 7H), 1.44 (m, 1H), 1.22 (m, 2H).

Example 92C3′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(8-aza-bicyclo[3.2.1]oct-8-yl)-phenyl]-amide

The title compound was prepared using the procedure described in Example49D using 4-(8-Aza-bicyclo[3.2.1]oct-8-yl)-phenylamine instead of4-ter-butylaniline. MS (ESI+) m/z 457 (M+H)⁺; 1H NMR (400 MHz,Methanol-D4) δ ppm 1.29 (m, 2H), 1.44 (m, 1H), 1.88 (m, 5H), 2.06 (m,2H), 2.61 (m, 2H), 3.46 (t, J=5.5 Hz, 2H), 4.01 (q, J=2.9 Hz, 2H), 4.17(s, 2H), 6.72 (m, 1H), 6.80 (d, J=8.9 Hz, 2H), 7.11 (dd, J=7.8, 4.8 Hz,1H), 7.39 (d, J=8.9 Hz, 2H), 8.00 (dd, J=7.8, 1.7 Hz, 1H), 8.45 (d,J=4.9 Hz, 1H).

Example 933′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(8-aza-bicyclo[3.2.1]oct-8-yl)-3-fluoro-phenyl]amide

The title compound was prepared using the procedure described in Example49D using 4-(8-aza-bicyclo[3.2.1]oct-8-yl)-3-fluoro-phenylamine insteadof 4-ter-butylaniline. MS (ESI+) m/z 475 (M+H)⁺, m/z 473 (M−H)⁻; 1H NMR(400 MHz, Methanol-D4) δ ppm 1.44 (m, 3H), 1.87 (m, 7 H), 2.60 (m, 2H),3.45 (t, J=5.5 Hz, 2H), 4.00 (q, J=3.0 Hz, 2H), 4.13 (s, 2H), 6.72 (m,1H), 6.89 (t, J=9.8 Hz, 1H), 7.10 (dd, J=7.8, 4.8 Hz, 1H), 7.20 (dd,J=8.7, 2.3 Hz, 1H), 7.42 (dd, J=15.6, 2.5 Hz, 1H), 7.99 (dd, J=7.8, 1.7Hz, 1H), 8.44 (dd, J=4.6, 1.2 Hz, 1H).

Example 943′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(8-aza-bicyclo[3.2.1]oct-8-yl)-3,5-difluoro-phenyl]amide

The title compound was prepared using the procedure described in Example49D using 4-(8-aza-bicyclo[3.2.1]oct-8-yl)-3,5-difluoro-phenylamineinstead of 4-ter-butylaniline. MS (ESI+) m/z 493 (M+H)⁺, m/z 491 (M−H)⁻;1H NMR (400 MHz, Methanol-D4) δ ppm 1.50 (m, 3H), 1.86 (m, 7H), 2.59 (m,2H), 3.44 (t, J=5.5 Hz, 2H), 4.00 (q, J=3.1 Hz, 2H), 4.03 (s, 2H), 6.71(m, 1H), 7.10 (dd, J=7.8, 4.8 Hz, 1H), 7.21 (d, J=12.9 Hz, 2H), 7.99(dd, J=7.8, 1.7 Hz, 1H), 8.44 (dd, J=4.6, 1.2 Hz, 1H).

Example 953′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-chloro-3-fluoro-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 3-fluoro-4-chloro-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 400 (M+H)⁺, m/z 398 (M−H)⁻; 1H NMR (400 MHz, CHLOROFORM-D) δppm 2.64 (m, 2H), 3.50 (t, J=5.5 Hz, 2H), 4.05 (q, J=3.1 Hz, 2H), 6.77(m, 1H), 6.99 (dd, J=7.8, 4.8 Hz, 1H), 7.16 (m, 1H), 7.31 (t, J=8.9 Hz,1H), 7.58 (s, 1H), 7.66 (dd, J=11.0, 2.5 Hz, 1H), 7.88 (dd, J=7.7, 1.8Hz, 1H), 8.42 (dd, J=4.6, 1.5 Hz, 1H).

Example 963′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-tert-butyl-3-fluoro-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 3-fluoro-4-tert-butyl-aniline instead of 4-ter-butylaniline.MS (ESI+) m/z 422 (M+H)⁺, m/z 420 (M−H)⁻; 1H NMR (400 MHz, CHLOROFORM-D)δ ppm 1.36 (s, 9H), 2.65 (m, 2H), 3.51 (t, J=5.5 Hz, 2H), 4.05 (q, J=3.1Hz, 2H), 6.76 (m, 1H), 6.98 (dd, J=7.4, 5.2 Hz, 1H), 7.11 (m, 1H), 7.23(t, J=8.7 Hz, 1H), 7.44 (m, 2H), 7.88 (dd, J=8.0, 1.8 Hz, 1H), 8.42 (dd,J=4.6, 1.2 Hz, 1H).

Example 973′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide

The title compound was prepared using the procedure described in Example49D using 4-(1-hydroxy-1-methyl-ethyl)-aniline instead of4-ter-butylaniline. MS (ESI+) m/z 406 (M+H)⁺ (80%), m/z 388 (M−17)⁺(100%), m/z 404 (M−H)⁻; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.57 (s,6H), 2.65 (m, 2H), 3.49 (t, J=5.4 Hz, 2H), 4.03 (q, J=3.0 Hz, 2H), 5.29(s, 1H), 6.75 (m, 1H), 6.98 (dd, J=7.4, 4.3 Hz, 1H), 7.44 (m, 2H), 7.51(m, 2H), 7.54 (s, 1H), 7.88 (dd, J=7.8, 1.7 Hz, 1H), 8.41 (dd, J=4.8,1.4 Hz, 1H).

Example 982-Methyl-2-{4-[(3′-trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carbonyl)-amino]-phenyl}-propionicacid methyl ester

The title compound was prepared using the procedure described in Example49D using 2-(4-Amino-phenyl)-2-methyl-propionic acid methyl esterinstead of 4-ter-butylaniline. MS (ESI+) m/z 448 (M+H)⁺, m/z 446 (M−H)⁻;1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.57 (s, 6H), 2.65 (m, 2H), 3.50(t, J=5.4 Hz, 2H), 3.64 (s, 3H), 4.04 (q, J=3.1 Hz, 2H), 6.75 (m, 1H),6.98 (dd, J=7.4, 5.2 Hz, 1H), 7.30 (m, 2H), 7.51 (m, 3H), 7.88 (dd,J=7.7, 1.8 Hz, 1H), 8.41 (dd, J=4.9, 1.2 Hz, 1H).

Example 99 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid [4-(8-aza-bicyclo[3.2.1]oct-8-yl)-3-fluoro-phenyl]-amide

The title compound was prepared using the procedure described in Example52B using 4-(8-aza-bicyclo[3.2.1]oct-8-yl)-3-fluoro-phenylamine insteadof 4-ter-butylaniline. MS (ESI+) m/z 408 (M+H)⁺, m/z 406 (M−H)⁻; 1H NMR(400 MHz, DMSO-D6) δ ppm 1.42 (m, 3H), 1.76 (m, 5H), 1.94 (m, 2H), 2.44(m, 2H), 3.91 (t, J=5.7 Hz, 2H), 4.14 (s, 2H), 4.35 (q, J=2.8 Hz, 2H),6.67 (t, J=4.8 Hz, 1H), 6.74 (m, 1H), 6.97 (t, J=9.5 Hz, 1H), 7.31 (dd,J=8.6, 2.1 Hz, 1H), 7.57 (dd, J=16.0, 2.5 Hz, 1H), 8.41 (d, J=4.6 Hz,2H), 9.69 (s, 1H).

Example 100 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid [4-(8-aza-bicyclo[3.2.1]oct-8-yl)-3,5-difluoro-phenyl]-amide

The title compound was prepared using the procedure described in Example52B using 4-(8-aza-bicyclo[3.2.1]oct-8-yl)-3,5-difluoro-phenylamineinstead of 4-ter-butylaniline. MS (ESI+) m/z 426 (M+H)⁺, m/z 424 (M−H)⁻;1H NMR (400 MHz, DMSO-D6) δ ppm 1.46 (m, 3H), 1.74 (m, 5H), 1.91 (m,2H), 2.44 (m, 2H), 3.91 (t, J=5.7 Hz, 2H), 3.97 (m, 2H), 4.35 (q, J=2.8Hz, 2H), 6.67 (t, J=4.8 Hz, 1H), 6.76 (m, 1H), 7.35 (d, J=13.5 Hz, 2H),8.40 (d, J=4.9 Hz, 2H), 9.78 (s, 1H).

Example 101 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-azepan-1-yl-phenyl)-amide

The title compound was prepared using the procedure described in Example52B using 4-azapan-1-yl-phenylamine instead of 4-ter-butylaniline. MS(ESI+) m/z 378 (M+H)⁺, m/z 376 (M−H)⁻; 1H NMR (400 MHz, DMSO-D6) δ ppm1.50 (s, 4H), 1.75 (s, 4H), 2.45 (m, 2H), 3.45 (m, 4H), 3.91 (t, J=5.7Hz, 2H), 4.33 (q, J=2.8 Hz, 2H), 6.67 (t, J=4.6 Hz, 1H), 6.73 (m, 3H),7.46 (d, J=8.9 Hz, 2H), 8.40 (d, J=4.6 Hz, 2H), 9.46 (s, 1H).

Example 102 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-amide

The title compound was prepared using the procedure described in Example49D using 2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-6-ylamineinstead of 4-ter-butylaniline. MS (ESI+) m/z 444 (M+H)⁺ (40%), m/z 330(M−113)⁺ (100%), m/z 442 (M−H)⁻; 1H NMR (400 MHz, DMSO-D6) δ ppm 2.56(m, 2H), 3.46 (t, J=5.5 Hz, 2H), 4.03 (q, J=2.9 Hz, 2H), 6.82 (m, 1H),7.00 (dd, J=7.7, 4.6 Hz, 1H), 7.43 (m, 1H), 7.57 (dd, J=9.2, 2.5 Hz,1H), 7.82 (dd, J=7.7, 1.5 Hz, 1H), 7.87 (d, J=2.5 Hz, 1H), 8.22 (dd,J=4.8, 1.7 Hz, 1H), 10.03 (s, 1H).

Example 103 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-tert-butyl-3-fluoro-phenyl)-amide

The title compound was prepared using the procedure described in Example52B using 4-tert-butyl-3-fluoro-aniline instead of 4-ter-butylaniline.MS (ESI+) m/z 355 (M+H)⁺ (90%), m/z 114 (M−240)⁺ (100%), m/z 353 (M−H)⁻;1H NMR (300 MHz, DMSO-D6) δ ppm 1.32 (s, 9H), 2.45 (m, 2H), 3.91 (t,J=5.6 Hz, 2H), 4.36 (q, J=2.4 Hz, 2H), 6.67 (t, J=4.7 Hz, 1H), 6.78 (m,1H), 7.25 (m, 2H), 7.38 (dd, J=8.5, 2.0 Hz, 1H), 7.57 (dd, J=15.3, 2.0Hz, 1H), 8.40 (d, J=4.7 Hz, 1H), 9.85 (s, 1H).

Example 1043′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-amide

The title compound was prepared using the procedure described in Example49D using 4-(2-hydroxy-1,1-dimethyl-ethyl)-aniline instead of4-ter-butylaniline. MS (ESI+) m/z 420 (M+H)⁺, m/z 418 (M−H)⁻; 1H NMR(300 MHz, CHLOROFORM-D) δ ppm 1.33 (s, 6H), 2.04 (s, 1H), 2.67 (m, 2H),3.53 (t, J=5.4 Hz, 2H), 3.60 (s, 2H), 4.07 (q, J=2.8 Hz, 2H), 6.77 (m,1H), 6.99 (dd, J=7.8, 4.7 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H), 7.41 (s, 1H),7.53 (d, J=8.8 Hz, 2H), 7.89 (dd, J=7.8, 1.7 Hz, 1H), 8.43 (d, J=4.7 Hz,1H).

Example 105 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-trifluoromethyl-phenyl)-amide

The title compound was prepared using the procedure described in Example52B using 4-trifluoromethyl-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 348 (M+H)⁺ (40%), m/z 367 (M+19)⁺ (100%), m/z 346 (M−H)⁻; 1HNMR (300 MHz, DMSO-D6) δ ppm 2.48 (m, 2H), 3.93 (t, J=5.8 Hz, 2H), 4.38(q, J=2.7 Hz, 2H), 6.67 (t, J=4.7 Hz, 1H), 6.84 (m, 1H), 7.68 (d, J=8.8Hz, 2H), 7.91 (d, J=8.5 Hz, 2H), 8.41 (d, J=4.7 Hz, 2H), 10.10 (s, 1H).

Example 106 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-chloro-3-fluoro-phenyl)-amide

The title compound was prepared using the procedure described in Example52B using 4-chloro-3-fluoro-aniline instead of 4-ter-butylaniline. MS(DCI+) m/z 333 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.47 (m, 2H),3.92 (t, J=5.6 Hz, 2H), 4.37 (q, J=2.9 Hz, 2H), 6.67 (t, J=4.7 Hz, 1H),6.81 (m, 1H), 7.52 (m, 2H), 7.85 (m, 1H), 8.40 (d, J=4.7 Hz, 2H), 10.05(s, 1H).

Example 1072-Methyl-2-{4-[(1-pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carbonyl)-amino]-phenyl}-propionicacid methyl ester

The title compound was prepared using the procedure described in Example52B using 4-propionic acid methyl ester-aniline instead of4-ter-butylaniline. MS (DCI+) m/z 381 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6)δ ppm 1.48 (s, 6H), 2.45 (m, 2H), 3.58 (s, 3H), 3.91 (t, J=5.6 Hz, 2H),4.35 (q, J=2.9 Hz, 2H), 6.67 (t, J=4.7 Hz, 1H), 6.77 (m, 1H), 7.24 (d,J=8.8 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 8.40 (d, J=4.7 Hz, 2H), 9.73 (s,1H).

Example 108 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(ethyl-isopropyl-amino)-phenyl]-amide hydrochloride

The title compound was prepared using the procedure described in Example49D using 4-(ethyl-isopropyl-amino)-phenylamine instead of4-ter-butylaniline. MS (ESI+) m/z 399 (M+H)⁺, m/z 397 (M−H)⁻; 1H NMR(300 MHz, DMSO-D6) δ ppm 0.99 (t, J=7.1 Hz, 3H), 1.11 (d, J=6.1 Hz, 3H),1.35 (d, J=5.8 Hz, 3H), 2.57 (s, 2H), 3.61 (m, 2H), 3.86 (s, 1H), 4.03(q, J=2.7 Hz, 2H), 6.84 (m, 1H), 7.01 (dd, J=7.8, 4.7 Hz, 1H), 7.66 (d,J=8.8 Hz, 2H), 7.84 (dd, J=7.8, 1.7 Hz, 1H), 7.90 (d, J=8.8 Hz, 2H),8.23 (dd, J=4.7, 1.4 Hz, 1H), 10.07 (s, 1H), 11.94 (s, 1H).

Example 1093′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-trifluoromethyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-trifluoromethyl-aniline instead of 4-ter-butylaniline. MS(ESI+) m/z 416 (M+H)⁺, m/z 414 (M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D) δppm 2.68 (m, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.08 (q, J=3.1 Hz, 2H), 6.81(m, 1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.54 (s, 1H), 7.60 (d, J=8.5 Hz,2H), 7.70 (d, J=8.5 Hz, 2H), 7.89 (dd, J=7.8, 1.7 Hz, 1H), 8.43 (dd,J=4.7, 1.4 Hz, 1H).

Example 1103′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-acetyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-acetyl-phenylamine instead of 4-ter-butylaniline. MS (ESI+)m/z 390 (M+H)⁺, m/z 388 (M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D) δ ppm2.59 (s, 3H), 2.68 (m, 2H), 3.52 (t, J=5.4 Hz, 2H), 4.08 (q, J=3.1 Hz,2H), 6.81 (m, 1H), 7.00 (dd, J=7.1, 4.7 Hz, 1H), 7.59 (s, 1H), 7.68 (d,J=8.8 Hz, 2H), 7.90 (dd, J=7.8, 1.7 Hz, 1H), 7.97 (d, J=8.5 Hz, 2H),8.43 (dd, J=4.7, 1.4 Hz, 1H).

Example 1114-[(3′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carbonyl)-amino]-benzoicacid methyl ester

The title compound was prepared using the procedure described in Example49D using 4-benzolic acid methyl ester-phenylamine instead of4-ter-butylaniline. MS (ESI+) m/z 406 (M+H)⁺, m/z 404 (M−H)⁻; 1H NMR(300 MHz, CHLOROFORM-D) δ ppm 2.68 (m, 2H), 3.52 (t, J=5.4 Hz, 2H), 3.90(s, 3H), 4.08 (q, J=3.1 Hz, 2H), 6.80 (m, 1H), 7.00 (dd, J=7.8, 5.8 Hz,1H), 7.56 (s, 1H), 7.66 (dt, J=9.0, 2.4, 2.2 Hz, 2H), 7.89 (dd, J=7.8,1.7 Hz, 1H), 8.03 (dt, J=9.0, 2.4, 2.2 Hz, 2H), 8.43 (dd, J=4.7, 1.4 Hz,1H).

Example 112 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide

The title compound was prepared using the procedure described in Example49D using 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamine instead of4-ter-butylaniline. MS (ESI+) m/z 398 (M+H)⁺, m/z 396 (M−H)⁻ (30%), m/z211 (M−186)⁻ (100%); 1H NMR (300 MHz, DMSO-D6) δ ppm 1.65 (s, 6H), 2.55(m, 2H), 3.46 (t, J=5.4 Hz, 2H), 3.65 (s, 4H), 4.04 (q, J=2.7 Hz, 2H),6.89 (m, 1H), 7.01 (dd, J=7.6, 4.6 Hz, 1H), 7.45 (d, J=9.8 Hz, 1H), 7.83(dd, J=7.6, 1.5 Hz, 1H), 8.18 (dd, J=10.0, 2.5 Hz, 1H), 8.22 (dd, J=4.7,1.7 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H), 10.08 (s, 1H).

Example 113 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(6-azepan-1-yl-pyridin-3-yl)-amide

The title compound was prepared using the procedure described in Example49D using 6-azepan-1-yl-pyridin-3-ylamine instead of 4-ter-butylaniline.MS (ESI+) m/z 412 (M+H)⁺, m/z 410 (M−H)⁻; 1H NMR (300 MHz, DMSO-D6) δppm 1.52 (m, 4H), 1.77 (s, 4H), 2.55 (m, 2H), 3.46 (t, J=5.4 Hz, 2H),3.69 (m, 4H), 4.03 (q, J=2.7 Hz, 2H), 6.89 (m, 1H), 7.01 (dd, J=7.8, 4.7Hz, 1H), 7.35 (d, J=9.5 Hz, 1H), 7.83 (dd, J=7.8, 1.7 Hz, 1H), 8.18 (dd,J=10.0, 2.5 Hz, 1H), 8.22 (dd, J=4.7, 1.7 Hz, 1H), 8.51 (d, J=2.4 Hz,1H), 10.08 (s, 1H).

Example 114 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-cyclopropyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-cyclopropane-aniline instead of 4-tert-butylaniline. MS(ESI+) m/z 354 (M+H)⁺, m/z 352 (M−H)⁻; 1H NMR (300 MHz, DMSO-D6) δ ppm0.61 (m, 2H), 0.90 (m, 2H), 1.86 (m, 1H), 2.55 (m, 2H), 3.45 (t, J=5.4Hz, 2H), 4.00 (q, J=2.5 Hz, 2H), 6.76 (m, 1H), 7.00 (m, 3H), 7.55 (m,2H), 7.82 (dd, J=7.8, 1.7 Hz, 1H), 8.22 (dd, J=4.7, 1.7 Hz, 1H), 9.63(s, 1H).

Example 115 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (6-trifluoromethyl-pyridin-3-yl)-amide

The title compound was prepared using the procedure described in Example49D using 6-trifluoromethyl-pyridin-3-ylamine instead of4-tert-butylaniline. MS (DCI+) m/z 350 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6)δ ppm 2.48 (m, 2H), 3.93 (t, J=5.8 Hz, 2H), 4.40 (q, J=2.9 Hz, 2H), 6.68(t, J=4.7 Hz, 1H), 6.91 (m, 1H), 7.88 (d, J=8.5 Hz, 1H), 8.40 (m, 3H),9.00 (d, J=2.4 Hz, 1H), 10.32 (s, 1H).

Example 116 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-acetyl-phenyl)-amide

The title compound was prepared using the procedure described in Example52B using 4-acetyl-aniline instead of 4-tert-butylaniline. MS (DCI+) m/z323 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.47 (m, 2H), 2.53 (s, 3H),3.92 (t, J=5.8 Hz, 2H), 4.37 (q, J=2.8 Hz, 2H), 6.67 (t, J=4.7 Hz, 1H),6.84 (m, 1H), 7.84 (m, 2H), 7.93 (m, 2H), 8.41 (d, J=4.7 Hz, 2H), 10.07(s, 1H).

Example 1174-[(1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carbonyl)-amino]-benzoicacid methyl ester

The title compound was prepared using the procedure described in Example52B using 4-amino-benzoic acid methyl ester instead of4-tert-butylaniline. MS (DCI+) m/z 339 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6)δ ppm 2.46 (m, 2H), 3.82 (s, 3H), 3.92 (t, J=5.8 Hz, 2H), 4.37 (q, J=2.7Hz, 2H), 6.67 (t, J=4.7 Hz, 1H), 6.83 (m, 1H), 7.84 (m, 2H), 7.92 (m,2H), 8.41 (d, J=4.7 Hz, 2H), 10.08 (s, 1H).

Example 1183′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-tert-butylsulfanyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-tert-butylsulfanyl-phenylamine instead of4-tert-butylaniline. MS (DCI+) m/z 436 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6)δ ppm 1.22 (s, 9H), 2.55 (m, 2H), 3.40 (t, J=5.6 Hz, 2H), 3.99 (q, J=2.7Hz, 2H), 6.78 (m, 1H), 7.18 (dd, J=7.8, 4.7 Hz, 1H), 7.42 (dt, J=8.8,2.7, 2.4 Hz, 2H), 7.72 (dt, J=9.0, 2.4, 2.2 Hz, 2H), 8.09 (dd, J=7.8,2.0 Hz, 1H), 8.52 (dd, J=4.7, 1.0 Hz, 1H), 9.88 (s, 1H).

Example 1193′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(6-trifluoromethyl-pyridin-3-yl)-amide

The title compound was prepared using the procedure described in Example49D using 6-trifluoromethyl-pyrid-3-ylamine instead of4-tert-butylaniline. MS (DCI+) m/z 417 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6)δ ppm 2.56 (m, 2H), 3.40 (t, J=5.4 Hz, 2H), 4.02 (q, J=2.9 Hz, 2H), 6.90(m, 1H), 7.19 (dd, J=7.8, 4.7 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 8.10 (dd,J=7.8, 1.7 Hz, 1H), 8.40 (dd, J=8.3, 2.2 Hz, 1H), 8.53 (dd, J=4.7, 1.4Hz, 1H), 9.01 (d, J=2.4 Hz, 1H), 10.31 (s, 1H).

Example 1203′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(2,2-difluoro-benzo[1,3]dioxol-5-yl)-amide

The title compound was prepared using the procedure described in Example49D using 2,2-difluoro-benzo[1,3]dioxol-5-ylamine instead of4-tert-butylaniline. MS (DCI+) m/z 428 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6)δ ppm 2.53 (m, 2H), 3.39 (t, J=4.8 Hz, 2H), 3.99 (q, J=2.7 Hz, 2H), 6.78(m, 1H), 7.18 (dd, J=7.8, 4.7 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.42 (m,1H), 7.82 (d, J=2.0 Hz, 1H), 8.09 (dd, J=7.8, 1.7 Hz, 1H), 8.52 (dd,J=4.7, 1.4 Hz, 1H), 9.94 (s, 1H).

Example 121 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid [4-(2-methyl-propane-2-sulfonyl)-phenyl]-amide

The title compound was prepared using the procedure described in Example52B using 4-(2-methyl-propane-2-sulfonyl)-phenylamine instead of4-tert-butylaniline. MS (DCI+) m/z 401 (M+H)⁺ (90%), m/z 231 (M−169)⁺(100%); 1H NMR (300 MHz, DMSO-D6) δ ppm 1.23 (s, 9H), 2.47 (m, 2H), 3.93(t, J=5.6 Hz, 2H), 4.38 (q, J=2.7 Hz, 2H), 6.68 (t, J=4.7 Hz, 1H), 6.86(m, 1H), 7.76 (m, 2H), 7.97 (m, 2H), 8.41 (d, J=4.7 Hz, 2H), 10.21 (s,1H).

Example 122 1-Pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-tert-butylsulfanyl-phenyl)-amide

The title compound was prepared using the procedure described in Example52B using 4-(2-methyl-propane-2-sulfanyl)-phenylamine instead of4-tert-butylaniline. MS (DCI+) m/z 369 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6)δ ppm 1.22 (s, 9H), 2.46 (m, 2H), 3.92 (t, J=5.8 Hz, 2H), 4.36 (q, J=2.7Hz, 2H), 6.67 (t, J=4.7 Hz, 1H), 6.79 (m, 1H), 7.42 (dt, J=9.1, 2.5, 2.3Hz, 2H), 7.71 (dt, J=9.1, 2.5, 2.3 Hz, 2H), 8.40 (d, J=4.7 Hz, 2H), 9.88(s, 1H).

Example 1233′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(2-methyl-propane-2-sulfonyl)-phenyl]-amide

The title compound was prepared using the procedure described in Example49D using 4-(2-methyl-propane-2-sulfonyl)-phenylamine instead of4-tert-butylaniline. MS (DCI+) m/z 468 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6)δ ppm 1.23 (s, 9H), 2.56 (m, 2H), 3.40 (t, J=5.1 Hz, 2H), 4.01 (m, 2H),6.84 (m, 1H), 7.19 (dd, J=7.8, 4.7 Hz, 1H), 7.76 (dt, J=9.0, 2.4, 2.2Hz, 2H), 7.97 (dt, J=9.0, 2.4, 2.2 Hz, 2H), 8.09 (dd, J=7.8, 1.7 Hz,1H), 8.53 (dd, J=4.7, 1.4 Hz, 1H), 10.20 (s, 1H).

Example 1241-(4-Methoxy-pyrimidin-2-yl)-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-trifluoromethyl-phenyl)-amide

MS (DCI+) m/z 379 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.47 (m, 2H),3.87 (s, 3H), 3.92 (t, J=5.6 Hz, 2H), 4.39 (q, J=2.6 Hz, 2H), 6.82 (m,1H), 7.68 (d, J=8.5 Hz, 3H), 7.91 (d, J=8.5 Hz, 2H), 8.13 (d, J=5.4 Hz,1H), 10.09 (s, 1H).

Example 125 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-trifluoromethanesulfonyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-(trifluoromethyl-sulfonyl)-phenylamine instead of4-tert-butylaniline. MS (ESI+) m/z 446 (M+H)⁺, m/z 444 (M−H)⁻; 1H NMR(300 MHz, CHLOROFORM-D) δ ppm 2.70 (m, 2H), 3.60 (t, J=5.4 Hz, 2H), 4.15(q, J=3.1 Hz, 2H), 6.88 (m, 2H), 7.65 (dd, J=7.8, 1.7 Hz, 1H), 7.81 (m,1H), 7.90 (m, 2H), 8.00 (m, 2H), 8.19 (dd, J=4.7, 1.7 Hz, 1H).

Example 126 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amide

The title compound was prepared using the procedure described in Example49D using4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenylamineinstead of 4-tert-butylaniline. MS (ESI+) m/z 480 (M+H)⁺, m/z 478(M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.68 (m, 2H), 3.45 (s, 1H),3.67 (t, J=5.8 Hz, 2H), 4.18 (q, J=2.7 Hz, 2H), 6.81 (m, 1H), 6.93 (dd,J=7.8, 5.1 Hz, 1H), 7.71 (m, 6H), 8.23 (dd, J=4.9, 1.5 Hz, 1H).

Example 127 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(2,2-dichloro-1-methyl-cyclopropyl)-phenyl]-amide

The title compound was prepared using the procedure described in Example49D using 4-(2,2-dichloro-1-methyl-cyclopropyl)-phenylamine instead of4-tert-butylaniline. MS (DCI+) m/z 436 (M+H)⁺ (70%), m/z 252 (M−183)⁺(100%); 1H NMR (300 MHz, DMSO-D6) δ ppm 1.61 (s, 3H), 1.74 (d, J=7.5 Hz,1H), 2.14 (d, J=7.8 Hz, 1H), 2.56 (m, 2H), 3.45 (t, J=5.4 Hz, 2H), 4.01(q, J=3.0 Hz, 2H), 6.77 (m, 1H), 7.00 (dd, J=7.6, 4.6 Hz, 1H), 7.27 (m,2H), 7.67 (m, 2H), 7.83 (dd, J=7.6, 1.5 Hz, 1H), 8.22 (dd, J=4.7, 1.7Hz, 1H), 9.75 (s, 1H).

Example 128 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(cyano-dimethyl-methyl)-phenyl]-amide

The title compound was prepared using the procedure described in Example49D using 4-(cyano-dimethyl-methyl)-phenylamine instead of4-tert-butylaniline. MS (DCI+) m/z 381 (M+H)⁺; 1H NMR (300 MHz,CHLOROFORM-D) δ ppm 1.72 (s, 6H), 2.69 (m, 2H), 3.59 (t, J=5.6 Hz, 2H),4.12 (q, J=2.9 Hz, 2H), 6.80 (m, 1H), 6.87 (dd, J=7.8, 4.7 Hz, 1H), 7.45(m, 2H), 7.49 (s, 1H), 7.59 (m, 2H), 7.63 (dd, J=7.6, 1.5 Hz, 1H), 8.19(dd, J=4.7, 1.7 Hz, 1H).

Example 1293′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(cyano-dimethyl-methyl)-phenyl]-amide

The title compound was prepared using the procedure described in Example49D using 4-(cyano-dimethyl-methyl)-phenylamine instead of4-tert-butylaniline. MS (ESI+) m/z 415 (M+H)⁺, m/z 414 (M−H)⁻ (18%), m/z212 (M−202)⁻ (100%); 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.72 (s, 6H),2.67 (m, 2H), 3.53 (t, J=5.4 Hz, 2H), 4.07 (q, J=3.1 Hz, 2H), 6.79 (m,1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.45 (m, 3H), 7.59 (m, 2H), 7.89 (dd,J=7.8, 2.0 Hz, 1H), 8.43 (dd, J=4.7, 2.0 Hz, 1H).

Example 1303′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(3-chloro-4-trifluoromethylsulfanyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 3-chloro-4-trifluoromethylsulfanyl-phenylamine instead of4-tert-butylaniline. MS (DCI+) m/z 482 (M+H)⁺ (45%), m/z 283 (M−198)⁺(100%); 1H NMR (300 MHz, DMSO-D6) δ ppm 2.54 (m, 2H), 3.39 (t, J=5.4 Hz,2H), 4.00 (q, J=2.4 Hz, 2H), 6.85 (m, 1H), 7.19 (dd, J=8.0, 4.6 Hz, 1H),7.81 (d, J=2.0 Hz, 1H), 7.83 (s, 1H), 8.09 (dd, J=8.0, 1.5 Hz, 1H), 8.16(d, J=2.0 Hz, 1H), 8.53 (dd, J=4.7, 1.4 Hz, 1H), 10.19 (s, 1H).

Example 131 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(8-aza-bicyclo[3.2.1]oct-8-yl)-3,5-difluoro-phenyl]-amide

The title compound was prepared using the procedure described in Example49D using 4-(8-aza-bicyclo[3.2.1]oct-8-yl)-3,5-difluoro-phenylamineinstead of 4-tert-butylaniline. MS (ESI+) m/z 459 (M+H)⁺, m/z 457(M−H)⁻; 1H NMR (300 MHz, DMSO) δ ppm 1.52 (m, 3H), 1.89 (m, 7H), 2.61(m, 2H), 3.53 (t, J=5.4 Hz, 2H), 4.05 (m, 4H), 6.75 (m, 1H), 6.94 (dd,J=7.8, 4.7 Hz, 1H), 7.22 (m, 2H), 7.73 (dd, J=7.8, 1.7 Hz, 1H), 8.16(dd, J=4.7, 1.7 Hz, 1H).

Example 1323′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-tert-butyl-2-chloro-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 2-chloro-4-tert-butyl-phenylamine instead of4-tert-butylaniline. MS (ESI+) m/z 438 (M+H)⁺, m/z 436 (M−H)⁻; 1H NMR(300 MHz, CHLOROFORM-D) δ ppm 1.30 (s, 9H), 2.69 (m, 2H), 3.55 (t, J=5.4Hz, 2H), 4.10 (q, J=3.1 Hz, 2H), 6.86 (m, 1H), 6.98 (dd, J=7.3, 5.3 Hz,1H), 7.31 (dd, J=8.8, 2.4 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.89 (dd,J=7.8, 1.7 Hz, 1H), 7.97 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 8.43 (dd,J=4.9, 1.5 Hz, 1H).

Example 133 1-Thiazol-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid(4-trifluoromethanesulfonyl-phenyl)-amide Example 133A1-Thiazol-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid

A mixture of 2-bromooxazole (4.98 mmol), and isoguvacine, sodium salt(1.2 g, 8.2 mmol) in water (7 mL) was heated to 90° C. and stirred for 4hour. Additional isoguvacine, sodium salt (0.52 g, 3.3 mmol) was thenadded and stirred overnight. The mixture was diluted with water andextracted with CH₂Cl₂. The aqueous layer was acidified with conc HCl(pH˜3) and extracted with CHCl₃. The organic layer was dried (Na₂SO₄)and concentrated under reduced pressure to provide1-Thiazol-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid a solid.

Example 133B 1-Thiazol-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid (4-trifluoromethanesulfonyl-phenyl)-amide

The title compound was prepared using the procedure described in Example52D using 4-trifluoromethanesulfonyl-phenylamine instead of4-tert-butylaniline. MS (DCI+) m/z 418 (M+H)⁺ (40%), m/z 243 (M−174)⁺(100%); 1H NMR (300 MHz, DMSO-D6) δ ppm 2.55 (m, 2H), 3.63 (t, J=5.8 Hz,2H), 4.15 (q, J=2.5 Hz, 2H), 6.87 (d, J=3.4 Hz, 2H), 7.20 (d, J=3.4 Hz,1H), 8.10 (m, 4H), 10.52 (s, 1H).

Example 134 1-Thiazol-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid(4-tert-butyl-phenyl)-amide

The title compound was prepared using the procedure described in Example52D. MS (DCI+) m/z 342 (M+H)⁺; 1H NMR (300 MHz, DMSO-D6) δ ppm 1.26 (s,9H), 2.53 (m, 2H), 3.62 (t, J=5.8 Hz, 2H), 4.10 (q, J=2.7 Hz, 2H), 6.74(m, 1H), 6.86 (d, J=3.7 Hz, 1H), 7.20 (d, J=3.7 Hz, 1H), 7.32 (d, J=8.8Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 9.71 (s, 1H).

Example 1353′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-dimethylsulfamoyl-phenyl)-amide

The title compound was prepared using the procedure described in Example52D using 4-dimethylsulfamoyl-phenylamine instead of4-tert-butylaniline. MS (ESI+) m/z 455 (M+H)⁺, m/z 453 (M−H)⁻; 1H NMR(300 MHz, CHLOROFORM-D) δ ppm 2.68 (m, 2H), 2.71 (s, 6H), 3.53 (t, J=5.4Hz, 2H), 4.09 (q, J=2.9 Hz, 2H), 6.83 (m, 1H), 7.02 (dd, J=7.8, 4.7 Hz,1H), 7.65 (s, 1H), 7.76 (s, 4H), 7.91 (dd, J=7.8, 1.7 Hz, 1H), 8.44 (dd,J=4.6, 1.5 Hz, 1H).

Example 1363′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid[4-(piperidine-1-sulfonyl)-phenyl]-amide

The title compound was prepared using the procedure described in Example52D using 4-(piperidine-1-sulfonyl 4-(piperidine-1-sulfonyl-phenylamineinstead of 4-tert-butylaniline. MS (ESI+) m/z 495 (M+H)⁺, m/z 493(M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.44 (m, 2H), 1.64 (m, 4H),2.68 (m, 2H), 2.98 (t, J=5.4 Hz, 4H), 3.54 (t, J=5.6 Hz, 2H), 4.10 (q,J=2.8 Hz, 2H), 6.82 (m, 1H), 7.02 (dd, J=7.5, 4.4 Hz, 1H), 7.67 (m, 1H),7.74 (s, 4H), 7.92 (dd, J=7.8, 1.7 Hz, 1H), 8.44 (dd, J=5.1, 1.4 Hz,1H).

Example 1373′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(5-iodo-pyridin-2-yl)-amide

The title compound was prepared using the procedure described in Example52D using 5-iodo-pyridin-2-ylamine instead of 4-tert-butylaniline. MS(ESI+) m/z 475 (M+H)⁺, m/z 473 (M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D) δppm 2.67 (m, 2H), 3.51 (t, J=5.4 Hz, 2H), 4.07 (q, J=3.1 Hz, 2H), 6.86(m, 1H), 6.99 (dd, J=7.8, 4.7 Hz, 1H), 7.89 (dd, J=7.8, 2.0 Hz, 1H),7.98 (dd, J=8.8, 2.4 Hz, 1H), 8.15 (m, 2H), 8.42 (dd, J=4.7, 1.4 Hz,1H), 8.47 (d, J=1.7 Hz, 1H).

Example 1383′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(3,4-difluoro-phenyl)-amide

The title compound was prepared using the procedure described in Example52D using 3,4-difluoro-phenylamine instead of 4-tert-butylaniline. MS(ESI+) m/z 384 (M+H)⁺, m/z 382 (M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D) δppm 2.65 (m, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.07 (q, J=3.1 Hz, 2H), 6.78(m, 1H), 7.00 (dd, J=7.8, 4.7 Hz, 1H), 7.12 (m, 2H), 7.41 (s, 1H), 7.68(m, 1H), 7.90 (dd, J=7.8, 1.7 Hz, 1H), 8.43 (dd, J=4.7, 1.4 Hz, 1H).

Example 139 3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-methanesulfonyl-phenyl)-amide

The title compound was prepared using the procedure described in Example49D using 4-methanesulfonyl-phenylamine instead of 4-tert-butylaniline.MS (DCI+) m/z 392 (M+H)⁺ (20%), m/z 206 (M−185)⁺ (100%); 1H NMR (300MHz, DMSO-D6) δ ppm 2.57 (m, 2H), 3.17 (s, 3H), 3.46 (t, J=5.4 Hz, 2H),4.04 (q, J=2.8 Hz, 2H), 6.87 (m, 1H), 7.01 (dd, J=7.8, 4.7 Hz, 1H), 7.85(m, 4H), 7.96 (dt, J=9.0, 2.4, 2.2 Hz, 2H), 8.23 (dd, J=4.6, 1.5 Hz,1H).

Example 1403′-Dimethylsulfamoyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-tert-butyl-phenyl)-amide Example 140A 2-Chloro-pyridine-3-sulfonicacid dimethylamide

A solution of Me₂NH in THF (2M, 8 mL, 16 mmol) was added to3-(2-chloropyridyl)sulfonyl chloride (J. Med. Chem. 1980, 23, 1376) (2.1g, 9.9 mmol) in THF (10 mL), and stirred 10 hours, quenched with sat aqNH₄Cl, extracted with EtOAc, and purified by flash chromatography (30%EtOAc/Hex) to provide sulfonamide as a red oil

Example 140B 1-Thiazol-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylicacid

A solution of 2-chloro-pyridine-3-sulfonic acid dimethylamide (1.18mmol) and isoguvacine, sodium salt (2.19 mmol) in THF (0.5 mL) and water(2 mL) was stirred at 90° C. for 22 hours, acidified (pH˜1) with TFA,and extracted with CH₂Cl₂. The organic layer was dried (Na₂SO₄),concentrated, and purified by flash chromatography (5% MeOH/CH₂Cl₂) andtrituration (Et₂O) to provide as a white solid. ¹H NMR (300 MHz, CD₃OD)δ 8.47 (dd, J=1.7, 4.8 Hz, 1H), 8.22 (dd, J=1.7, 7.8 Hz, 1H), 7.22 (dd,J=4.8, 7.8 Hz, 1H), 7.03 (sept, J=1.7 Hz, 1H), 3.99 (q, J=3.0 Hz, 2H),3.40 (t, J=5.6 Hz, 2H), 2.73 (s, 6H), 2.56 (m, 2H).

Example 140C3′-Dimethylsulfamoyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-tert-butyl-phenyl)-amide

The title compound was prepared using the procedure described in Example52D using 4-tert-butylaniline. MS (ESI+) m/z 443 (M+H)⁺, m/z 441 (M−H)⁻;1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.31 (s, 9H), 2.73 (s, 2H), 2.77(s, 6H), 3.56 (t, J=5.6 Hz, 2H), 4.08 (q, J=2.9 Hz, 2H), 6.84 (m, 1H),7.10 (dd, J=7.8, 4.7 Hz, 1H), 7.36 (m, 2H), 7.39 (d, J=2.0 Hz, 1H), 7.49(m, 2H), 8.18 (dd, J=8.0, 1.9 Hz, 1H), 8.45 (dd, J=4.7, 2.0 Hz, 1H).

Example 1413′-Dimethylsulfamoyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-chloro-phenyl)-amide

The title compound was prepared using the procedure described in Example52D using 4-chloro-phenylamine instead of 4-tert-butylaniline. MS (ESI+)m/z 421 (M+H)⁺, m/z 419 (M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D) δ ppm2.72 (s, 2H), 2.77 (s, 6H), 3.56 (t, J=5.4 Hz, 2H), 4.08 (d, J=2.4 Hz,2H), 6.86 (s, 1H), 7.10 (dd, J=8.0, 4.6 Hz, 1H), 7.31 (d, J=8.8 Hz, 2H),7.43 (s, 1H), 7.54 (d, J=9.2 Hz, 2H), 8.17 (dd, J=7.8, 1.4 Hz, 1H), 8.45(dd, J=4.6, 1.5 Hz, 1H).

Example 1423′-Dimethylsulfamoyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(4-trifluoromethoxy-phenyl)-amide

The title compound was prepared using the procedure described in Example52D using 4-trifluoromethoxy-phenylamine instead of 4-tert-butylaniline.MS (ESI+) m/z 471 (M+H)⁺, m/z 469 (M−H)⁻; 1H NMR (300 MHz, CHLOROFORM-D)δ ppm 2.72 (s, 2H), 2.77 (s, 6H), 3.57 (t, J=5.3 Hz, 2H), 4.09 (s, 2H),6.87 (s, 1H), 7.11 (dd, J=7.8, 4.4 Hz, 1H), 7.20 (d, J=8.1 Hz, 2H), 7.48(s, 1H), 7.62 (d, J=8.8 Hz, 2H), 8.18 (d, J=7.5 Hz, 1H), 8.46 (d, J=3.7Hz, 1H).

(5) Biological Data (a) In Vitro Data—Determination of InhibitionPotencies

Dulbecco's modified Eagle medium (D-MEM) (with 4.5 mg/mL glucose) andfetal bovine serum were obtained from Hyclone Laboratories, Inc. (Logan,Utah). Dulbecco's phosphate-buffered saline (D-PBS) (with 1 mg/mLglucose and 3.6 mg/l Na pyruvate, without phenol red), L-glutamine,hygromycin B, and Lipofectamine™ were obtained from Life Technologies(Grand Island, N.Y.). G418 sulfate was obtained fromCalbiochem-Novabiochem Corp. (San Diego, Calif.). Capsaicin(8-methyl-N-vanillyl-6-nonenamide) was obtained from Sigma-Aldrich, Co.(St. Louis, Mo.). Fluo-4 AM(N-[4-[6-[(acetyloxy)methoxy]-2,7-difluoro-3-oxo-3H-xanthen-9-yl]-2-[2-[2-[bis[2-[(acetyloxy)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-N-[2-[(acetyloxy)methoxy]-2-oxyethyl]-glycine,(acetyloxy)methyl ester) was purchased from Molecular Probes (Eugene,Oreg.).

The cDNAs for the human VR1 receptor were isolated by reversetranscriptase-polymerase chain reaction (RT-PCR) from human smallintestine poly A+RNA supplied by Clontech (Palo Alto, Calif.) usingprimers designed surrounding the initiation and termination codonsidentical to the published sequences (Hayes et al. Pain Vol. 88 pages205-215, 2000). The resulting cDNA PCR products were subcloned intopCIneo mammalian expression vector (Promega) and fully sequenced usingfluorescent dye-terminator reagents (Prism, Perkin-Elmer AppliedBiosystems Division) and a Perkin-Elmer Applied Biosystems Model 373 DNAsequencer or Model 310 genetic analyzer. Expression plasmids encodingthe hVR1 cDNA were transfected individually into 1321N1 humanastrocytoma cells using Lipofectamine™. Forty-eight hours aftertransfection, the neomycin-resistant cells were selected with growthmedium containing 800 μg/mL Geneticin (Gibco BRL). Surviving individualcolonies were isolated and screened for VR1 receptor activity. Cellsexpressing recombinant homomeric VR1 receptors were maintained at 37° C.in D-MEM containing 4 mM L-glutamine, 300 μg/mL G418 (Cal-biochem) and10% fetal bovine serum under a humidified 5% CO₂ atmosphere.

The functional activity of compounds at the VR1 receptor was determinedwith a Ca²⁺ influx assay and measurement of intracellular Ca²⁺ levels([Ca²⁺]i). All compounds were tested over an 11-point half-logconcentration range. Compound solutions were prepared in D-PBS (4× finalconcentration), and diluted serially across 96-well v-bottom tissueculture plates using a Biomek 2000 robotic automation workstation(Beckman-Coulter, Inc., Fullerton, Calif.). A 0.2 μM solution of the VR1agonist capsaicin was also prepared in D-PBS. The fluorescent Ca²⁺chelating dye fluo-4 was used as an indicator of the relative levels of[Ca²⁺]i in a 96-well format using a Fluorescence Imaging Plate Reader(FLIPR) (Molecular Devices, Sunnyvale, Calif.). Cells were grown toconfluency in 96-well black-walled tissue culture plates. Then, prior tothe assay, the cells were loaded with 100 μL per well of fluo-4 AM (2μM, in D-PBS) for 1-2 hours at 23° C. Washing of the cells was performedto remove extracellular fluo-4 AM (2×1 mL D-PBS per well), andafterward, the cells were placed in the reading chamber of the FLIPRinstrument. 50 μL of the compound solutions were added to the cells atthe 10 second time mark of the experimental run. Then, after a 3 minutetime delay, 50 μL of the capsaicin solution was added at the 190 secondtime mark (0.05 μM final concentration)(final volume=200 μL) tochallenge the VR1 receptor. Time length of the experimental run was 240seconds. Fluorescence readings were made at 1 to 5 second intervals overthe course of the experimental run. The peak increase in relativefluorescence units (minus baseline) was calculated from the 190 secondtime mark to the end of the experimental run, and expressed as apercentage of the 0.05 μM capsaicin (control) response. Curve-fits ofthe data were solved using a four-parameter logistic Hill equation inGraphPad Prism® (GraphPad Software, Inc., San Diego, Calif.), and IC₅₀values were calculated.

The compounds of the present invention were found to be antagonists ofthe vanilloid receptor subtype 1 (VR1) receptor with IC_(50s) from about2200 nM to about 0.5 nM. In a preferred range, compounds tested hadIC_(50s) from about 200 nM to about 1.0 nM.

(a) In Vivo Data—Analgesic Effects

Experiments were performed on 400 adult male 129J mice (JacksonLaboratories, Bar Harbor, Me.), weighing 20-25 g and male Sprague-Dawleyrats (Charles River, Wilmington, Mass.) weighing 200-300 grams wereutilized. Animals were kept in a vivarium, maintained at 22° C., with a12 hour alternating light-dark cycle with food and water available adlibitum. All experiments were performed during the light cycle. Animalswere randomly divided into separate groups of 6 animals each. Eachanimal was used in one experiment only and was sacrificed immediatelyfollowing the completion of the experiment. All animal handling andexperimental procedures were approved by an IACUC Committee.

The antinociceptive test used was a modification of the abdominalconstriction assay described in Collier, et al., Br. J. Pharmacol.Chemother. 32 (1968) 295-310. Each animal received an intraperitoneal(i.p.) injection of 0.3 mL of 0.6% acetic acid in normal saline to evokewrithing. Animals were placed separately under clear cylinders for theobservation and quantification of abdominal constriction. Abdominalconstriction was defined as a mild constriction and elongation passingcaudally along the abdominal wall, accompanied by a slight twisting ofthe trunk and followed by bilateral extension of the hind limbs. Thetotal number of abdominal constrictions was recorded from 5 to 20minutes after acetic acid injection. The ED_(50s) were determined basedon the i.p. injection.

The other antinociceptive test used was Complete Freund'sAdjuvant-induced Thermal Hyperalgesia (CFA) assay described in Pircio etal. (Eur J. Pharmacol. Vol. 31 (2) pages 207-15, 1975). Chronicinflammatory hyperalgesia was induced in one group of rats following theinjection of complete Freund's adjuvant (CFA, 50%, 150 ul) into theplantar surface of the right hindpaw 48 hours prior to testing. Thermalnociceptive thresholds were measured in three different groups of rats.The ED_(50s) were determined based on the oral administration.

The compounds of the present invention tested were found to haveantinociceptive effects with ED_(50s) from about 1 mg/kg to about 500mg/kg.

The in vitro and in vivo data demonstrates that compounds of the presentinvention antagonize the VR1 receptor and are useful for treating pain.

Compounds of the present invention are also useful for ameliorating orpreventing additional disorders such as, but not limited to,inflammatory thermal hyperalgesia, bladder overactivity, and urinaryincontinence as described by Nolano, M. et al., Pain 81 (1999) 135;Caterina, M. J. and Julius, D., Annu. Rev. Neurosci. 24, (2001) 487-517;Caterina, M. J. et al., Science 288 (2000) 306-313; Caterina, M. J. etal., Nature 389 (1997) 816-824; Fowler, C. Urology 55 (2000) 60; andDavis, J. et al., Nature 405 (2000) 183-187.

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention. The pharmaceuticalcompositions comprise compounds of the present invention formulatedtogether with one or more non-toxic pharmaceutically acceptablecarriers.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracistemally, intravaginally, topically (as by powders, ointments ordrops), bucally or as an oral or nasal spray. The term “parenterally,”as used herein, refers to modes of administration, which includeintravenous, intramuscular, intraperitoneal, intrasternal, subcutaneousand intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier,” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such as propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents, which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions that are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable carrier or excipient, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants that may berequired. Opthalmic formulations, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) which is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the present invention can be employedin pure form or, where such forms exist, in pharmaceutically acceptablesalt, ester or prodrug form. The phrase “therapeutically effectiveamount” of the compound of the invention means a sufficient amount ofthe compound to treat disorders, at a reasonable benefit/risk ratioapplicable to any medical treatment. It will be understood, however,that the total daily usage of the compounds and compositions of thepresent invention will be decided by the attending physician within thescope of sound medical judgement. The specific therapeutically effectivedose level for any particular patient will depend upon a variety offactors including the disorder being treated and the severity of thedisorder; activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts.

The term “pharmaceutically acceptable salt,” as used herein, means saltsderived from inorganic or organic acids. The salts can be prepared insitu during the final isolation and purification of compounds of formula(I-VII) or separately by reacting the free base of a compound of formula(I-VII) with an inorganic or organic acid. Representative acid additionsalts include, but are not limited to, acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,dihydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate(isethionate), lactate, maleate, fumarate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate,(L) tartrate, (D) tartrate, (DL) tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate, and undecanoate.

The term “pharmaceutically acceptable ester,” as used herein, meansesters of compounds of the present invention which hydrolyze in vivo andinclude those that break down readily in the human body to leave theparent compound or a salt thereof. Examples of pharmaceuticallyacceptable, non-toxic esters of the present invention include C₁-to-C₆alkyl esters and C₅-to-C₇ cycloalkyl esters, although C₁-to-C₄ alkylesters are preferred. Esters of the compounds of formula (I-VII) may beprepared according to conventional methods.

The term “pharmaceutically acceptable amide,” as used herein, means tonon-toxic amides of the present invention derived from ammonia, primaryC₁-to-C₆ alkyl amines and secondary C₁-to-C₆ dialkyl amines. In the caseof secondary amines, the amine may also be in the form of a 5- or6-membered heterocycle containing one nitrogen atom. Amides derived fromammonia, C₁-to-C₃ alkyl primary amides and C₁-to-C₂ dialkyl secondaryamides are preferred. Amides of the compounds of formula (I-VII) may beprepared according to conventional methods.

The term “pharmaceutically acceptable prodrug” or “prodrug,” as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like.Prodrugs of the present invention may be rapidly transformed in vivo tocompounds of formula (I-VII), for example, by hydrolysis in blood.

The present invention contemplates compounds of formula (I-VII) formedby synthetic means or formed by in vivo biotransformation.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

The total daily dose of the compounds of this invention administered toa human or lower animal may range from about 0.01 to about 150mg/kg/day. For purposes of oral administration, more preferable dosescan be in the range of from about 0.1 to about 150 mg/kg/day. Ifdesired, the effective daily dose can be divided into multiple doses forpurposes of administration; consequently, single dose compositions maycontain such amounts or submultiples thereof to make up the daily dose.

1. A compound of formula (VII)

wherein X₁ is N or CR₁; X₅ is N or CR₅; X₆ is a bond or CR₆; X₇ is N orCR₇; X₈ is N or CR₈; X₉ is N or CR₉; R₁, R₅, and R₉ are independentlyselected from the group consisting of hydrogen, alkyl, alkoxy, halogen,haloalkyl and heterocycle; R₇ is hydrogen, alkenyl, alkoxy,alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl,alkoxycarbonylalkyl, alkylsulfonyl, alkylthio, alkynyl, aryl, arylalkyl,aryloxy, arylthio, cyanoalkyl, cycloalkyl, cycloalkylalkyl,cycloalkyloxy, cycloalkylthio, haloalkoxy, haloalkyl, haloalkylsulfonyl,haloalkylthio, halogen, heteroaryl, heteroarylalkyl, heteroaryloxy,heteroarylthio, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl,R_(C)R_(D)N—, (R_(A)R_(B)N)carbonyl-, (R_(A)R_(B)N)sulfonyl-; orR_(A)S(O)₂—; R₆ and R₈ are independently hydrogen, lower alkenyl, loweralkoxy, lower alkyl, lower alkylthio, lower alkynyl, lower haloalkoxy,lower haloalkyl, lower haloalkylthio, halogen, hydroxy, mercapto, orR_(A)R_(B)N—; R_(A) and R_(B) are independently alkyl, hydrogen,haloalkyl, or heterocycle; and R_(C) and R_(D) are independentlyhydrogen, alkenyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, or(NR_(A)R_(B))carbonyl.
 2. A compound according to claim 1, wherein X₁ isCR₁; X₅ is CR₅; X₆ is CR₆; X₇ is CR₇; X₈ is CR₈; X₉ is N or CR₉; R₇ andR₈ are independently selected from the group consisting of hydrogen,alkyl, and halogen.
 3. A compound according to claim 2 that is3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(5-fluoro-pyridin-2-yl)-amide;3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(5-chloro-pyridin-2-yl)-amide;3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(5-bromo-pyridin-2-yl)-amide;3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(5-iodo-pyridin-2-yl)-amide; or3′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(5-iodo-pyridin-2-yl)-amide.
 4. The compound according to claim 1,wherein X₁ is CR₁; X₅ is CR₅; X₆ is CR₆; X₇ is CR₇; X₈ is N; X₉ is CR₉;R₅, R₆, R₉ and R₁, are independently selected from the group consistingof hydrogen, alkyl, haloalkyl, and halogen; R₇ is hydrogen, alkenyl,alkoxy, alkoxycarbonyl, alkoxysulfonyl, alkyl, alkylcarbonyl,alkoxycarbonylalkyl, alkylsulfonyl, alkylthio, alkynyl, aryl, arylalkyl,aryloxy, arylthio, cyanoalkyl, cycloalkyl, cycloalkylalkyl,cycloalkyloxy, cycloalkylthio, haloalkoxy, haloalkyl, haloalkylsulfonyl,haloalkylthio, halogen, heteroaryl, heteroarylalkyl, heteroaryloxy,heteroarylthio, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl,R_(C)R_(D)N—, (R_(A)R_(B)N)carbonyl-, (R_(A)R_(B)N)sulfonyl-; orR_(A)S(O)₂—; R_(A) and R_(B) are independently alkyl, hydrogen,haloalkyl, or heterocycle; and R_(C) and R_(D) are independentlyhydrogen, alkenyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, or(NR_(A)R_(B))carbonyl-.
 5. A compound according to claim 4 that is3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(6-trifluoromethyl-pyridin-3-yl)-amide;3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(6-chloro-pyridin-3-yl)-amide;3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide;3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(6-azepan-1-yl-pyridin-3-yl)-amide; or3′-Trifluoromethyl-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(6-trifluoromethyl-pyridin-3-yl)-amide.
 6. The compound according toclaim 1, wherein wherein X₁ is CR₁; X₅ is CR₅; X₆ is a bond; X₇ is N; X₈is N; X₉ is CR₉; R₁, R₉ and R₅, are independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, and halogen.
 7. Thecompound according to claim 6 that is3′-Chloro-3,6-dihydro-2H-[1,2′]bipyridinyl-4-carboxylic acid(1-tert-butyl-1H-pyrazol-4-yl)-amide.
 8. A compound according to claim 1X₁ is N; X₅ is CR₅; X₆ is CR₆; X₇ is CR₇; X₈ is N; X₉ is CR₉; R₆, R₇, R₉and R₅, are independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, and halogen.
 9. A compound according toclaim 8 that is1-pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid(6-trifluoromethyl-pyridin-3-yl)-amide
 10. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula(VII) according to claim 1 or a pharmaceutically acceptable saltthereof.
 11. A method of treating pain in a mammal, comprisingadministering a therapeutically effective amount of a compound offormula (VII) according to claim 1 or a pharmaceutically acceptable saltthereof.